1,3-Di-oxo-indene derivative, pharmaceutically acceptable salt or optical isomer thereof, preparation method thereof, and pharmaceutical composition containing same as an antiviral, active ingredient

ABSTRACT

Disclosed are 1,3-Dioxoindene derivatives, pharmaceutically acceptable salts thereof or enantiomers, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of viral diseases, comprising the same as an active ingredient. The 1,3-Dioxoindene derivatives have excellent inhibitory activity against picornaviruses including coxsackie-, entero-, echo-, Polio-, and rhinoviruses, as well as exhibiting low cytotoxicity, so that they can be useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of viral diseases including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.

TECHNICAL FIELD

The present invention relates to 1,3-Dioxoindene derivatives,pharmaceutically acceptable salts thereof or enantiomers thereof,preparation methods thereof, and pharmaceutical compositions for theprevention and treatment of viral diseases, comprising the same.

BACKGROUND ART

Picornaviruses are non-enveloped, positive single-stranded RNA viruseswith an RNA genome 7.2-8.5 Kb long. These viruses are very small andglobular in shape with a size of about 22˜30 nm, and were firstidentified a long time ago. Among the viruses belonging to the familyPicornaviridae are enteroviruses including rhinovirus, poliovirus,coxsackievirus A, coxsackievirus B, and echovirus, and hepatitis Avirus.

The diseases that picornaviruses cause are varied, ranging fromrespiratory diseases to digestive diseases, to circulatory diseases andto dermal diseases, examples of which include poliomyelitis, paralysis,acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouthdisease, vesicular disease, hepatitis A, myositis, myocarditis,pancreatitis, diabetes, epidemic myalgia, encephalitis, cold,herpangina, and foot-and-mouth disease. However, there are notherapeutics for curing these diseases. Most of the drugs underdevelopment are uncoating inhibitors. Viruses belonging to the familyPicornaviridae cause various diseases including the aforementionedrespiratory diseases, which evoke hygienic, social and economic issues.Picornaviruses are the main causative agents of waterborne diseases.Being very stable and difficult to disinfect, the RNA virusesincessantly cause related diseases.

Human rhinoviruses (hRV) have been recently associated with the majorityof asthma exacerbations, and are known to exist even in bronchialtissues of many stable asthma patients. Comparison of respectivebronchial mucosa biopsy specimens taken from asthma and non-asthmapatients showed significantly higher frequencies of detection of humanrhinoviruses in the lower respiratory tract of asthma patients, comparedto non-asthma patients. It has also been reported that there iscorrelation between the presence of human rhinovirus and the clinicalseverity of asthma. In addition, rhinoviruses cause chronic obstructivepulmonary disease, pneumonia, sinusitis, and otitis media as well asasthma.

Rhinoviruses are the main causative of the common cold whileenterovirus-induced diseases include meningitis, respectory tractinfection, etc. Extensive effort to provide vaccination againstpoliovirus has significantly reduced the onset of poliomyelitisworldwide, but there are still reports of cases of the disease in Niger,Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A is nowpossible to control to some degree thanks to vaccines for hepatitis Aviruses. However, no vaccines for coxsackieviruses, echoviruses, orrhinoviruses have been developed, thus far.

Particularly, coxsackievirus B is a main cause of myocarditis, which maydevelop, in serious cases, into idiopathic dilated cardiomyopathy, whichrequires heart transplantation

Enviroxime derivatives are considered the most promising candidate witha broad anti-enterovirus- and anti-rhinovirus activity. Enviroximeinterferes with the synthesis of plus-strand RNA by binding to the virusprotein 3A that is required for the formation of RNA intermediates inthe virus reproduction (Heinz B A and Vance L M: J Virol, 1995, 69(7),4189-97). In clinical studies, however, the compound was observed tohave insignificant or few therapeutic effects, with the concomitantdetection of bad pharmacokinetics and unwanted side effects (Miller F Det al.: Antimicrob Agents Chemother, 1985, 27(1), 102-6).

The protease inhibitor AG 7088 has been developed on the basis of theknowledge about the fine structure and function of the viral protease2C. In the cell culture in the nanomolar concentration range, AG 7088has an effect against 48 rhinovirus types and coxsackievirus A21, B3,enterovirus 70 and echovirus 11 (Pattick A K et al.: AntimicrobilaAgents Chemother, 1999, 43(10), 2444-50).

Thanks to the clarification of the molecular structure of the viralcapsids, the preconditions for a purposeful design of capsid blockers,the “WIN substances”, have been obtained (Diana G D: Curr Med Chem 2003,2, 1-12). They inhibit the adsorption and/or the uncoating ofrhinoviruses and enteroviruses. Some of the WIN substances have a highlyspecific effect only against individual genera or virus types of thepicornaviruses. Other derivatives inhibit the replication both ofrhinoviruses and enteroviruses. Arildone, disoxaril and pirodavirbelong, for example, to the WIN substances. These compounds showed verygood antiviral effects in the cell culture. However, a poor solubility(arildone), low bioavailability (arildone and disoxaril), a rapidmetabolization and excretion (disoxaril and WIN 54954) as well as sideeffects, such as skin rash (WIN 54954), made a clinical applicationimpossible.

Pleconaril, a kind of WIN substance, has a very good oralbioavailability and after its binding to the hydrophobe pocket in theviruscapsid, it inhibits the penetration of rhino-, echo- andcoxsackieviruses (Pevear D C et al.: Antimicrob Agents Chemother 1999,43(9), 2109-15; McKinlay M A et al.: Annu Rev Microbiol 1992, 46,635-54). Therefore, pleconaril is potentially effective against a broadspectrum of virus diseases, ranging from the common cold to the viralmeningitis or myocarditis. Resistances were observed for rhinoviruses,enterovirus 71 and coxsackievirus B3 (Ledford R M et al.: J Virol 2004,78(7), 3663-74; Groarke J M et al.: J Infect Dis 1999, 179(6), 1538-41).However, the proven therapeutic effect was not sufficient for theregistration of pleconaril (Picovir, Viropharma, USA) as an agent forthe treatment of rhinovirus infections in the USA. In March 2002, acorresponding application was refused by the Food and DrugAdministration (FDA) because therapy success was too low and sideeffects were observed.

BTA-798 was found to have higher antiviral activity than pleconaril, asevaluated in vitro and in vivo with rhinoviruses, and is now being undera clinical test (Ryan, J. et al. Antiviral Res [18th Intl Conf AntiviralRes (April 11-14, Barcelona) 2005] 2005, 65(3): Abst LB-11).

However, no antiviral drugs that have gained approval for use in thetreatment of entero- or rhinoviruses have been developed, so far.

Leading to the present invention, intensive and thorough research intoeffective virustatics against picornaviruses including coxsackie-,entero-, echo-, polio-, and rhinoviruses, culminated in the finding thatnovel 1,3-Dioxoindene derivatives exhibit highly inhibitory activityagainst picornaviruses including coxsackie-, entero-, echo-, polio-, andrhinoviruses.

DISCLOSURE Technical Problem

It is therefore an object of the present invention to provide a1,3-Dioxoindene derivative, or a pharmaceutically acceptable saltthereof.

It is another object of the present invention to provide a method forthe preparation of the 1,3-Dioxoindene derivative, or pharmaceuticallyacceptable salt thereof.

It is a further object of the present invention to provide apharmaceutical composition for the prevention or treatment of a viraldisease, comprising the 1,3-Dioxoindene derivative, or pharmaceuticallyacceptable salt thereof as an active ingredient.

Technical Solution

In accordance with an aspect thereof, the present invention provides an1,3-Dioxoindene derivative represented by the following Chemical Formula1, a pharmaceutically acceptable salt thereof, or an enantiomer thereof:

(wherein,

A¹, A², A³, A⁴, D¹, D², D³, D⁴, Z¹, Z², Z³, X, Y, E and G arerespectively as defined in the following description of thespecification.)

In accordance with another aspect thereof, the present inventionprovides a method for the preparation of the 1,3-Dioxoindene derivative,pharmaceutically acceptable salt or enantiomer.

In accordance with a further aspect thereof, the present inventionprovides a pharmaceutical composition for the prevention or treatment ofa viral disease, comprising the 1,3-Dioxoindene derivative,pharmaceutically acceptable salt or enantiomer as an active ingredient.

Advantageous Effects

Having excellent inhibitory activity against picornaviruses includingcoxsackie-, entero-, echo-, Polio-, and rhinoviruses, as well asexhibiting low cytotoxicity, the 1,3-Dioxoindene derivative of ChemicalFormula 1 can be useful as an active ingredient of a pharmaceuticalcomposition for the prevention or treatment of viral diseases includingpoliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viralmeningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A,myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia,encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronicobstructive pulmonary disease, pneumonia, sinusitis or otitis media.

BEST MODE

Below, a detailed description will be given of the present invention.

According to one aspect thereof, the present invention addresses1,3-Dioxoindene derivatives expressed by Formula 1,pharmaceutically-acceptable salt thereof or optical isomer thereof:

wherein,

A¹, A², A³ and A⁴ are, either independently or optionally, any oneselected from a group consisting of —H, halogen, —OH, —CN, —N₃, C₁˜C₁₀alkoxy, C₁˜C₁₀ straight- or branched-chain alkyl, C₆˜C₁₂ aryl,—O(C═O)R¹, —(C═O)R¹, —(C═O)OR¹, —O(C═O)OR¹, —O(C═O)NR¹R², —NO₂, —NR¹R²,—NR¹(C═O)R², —NR¹(C═S)R², —NR¹(C═O) OR², —NR¹(C═O)—NR²R³ and—NR¹(C═S)—NR²R³, or two or more neighboring substituents A, A2, A³ andA⁴ may form a ring together, wherein a ring formed by two or moreneighboring substituents A¹, A², A³ and A⁴ may include one or morehetero atom, and the hetero atom is N, O or S; G is —H, halogen, —OH,—CN, —N₃, C₁˜C₁₀ alkoxy, —O(C═O)R, —(C═O)R, —(C═O)OR¹, —O(C═O)OR¹,—O(C═O)NR¹R², —NO₂, —NR¹R², —NR¹(C═O)R², —NR¹(C═S)R², —NR¹(C═O) OR²,—NR¹(C═O)—NR²R³, —NR¹(C═S)—NR²R³ or

D¹, D², D³ and D⁴ are, either independently or optionally, any oneselected from a group consisting of —H, halogen, —OH, —CN, C₁˜C₁₀alkoxy, C₁˜C₁₀ straight- or branched-chain alkyl, C₆˜C₁₂ aryl,—(CH₂)_(n)—(C═O) OR¹, —O(C═O)R, —(C═O)R, —(C═O)OR, —O(C═O)OR,—O(C═O)NR¹R², —NO₂, —NR¹R², —NR¹(C═O)R², —NR¹(C═S)R², —NR¹(C═O) OR²,—NR¹(C═O)—NR²R³, —SR¹ and —NR¹(C═S)—NR²R³, or two or more neighboringsubstituents D¹, D², D³ and D⁴ may form a ring together, a ring formedby two or more neighboring substituent D¹, D², D³ and D⁴ may include oneor more hetero atom, and the hetero atom is N, O or S;

E is —H, —OH, —OR¹, —O(C═O)R¹, —(C═O)R¹, —(C═O)OR¹, —O(C═O)OR,—O(C═O)NR¹R², —NO₂, —NR¹R², —NR¹(C═O)R², —SR, —NR¹(C═S)R², —NR¹(C═O)OR², —NR¹(C═O)—NR²R³ or —NR¹(C═S)—NR²R;

R¹, R² and R³ are, each independently, hydrogen, nonsubstituted orphenyl-substituted C₁˜C₁₀ straight- or branched-chain alkyl, C₁˜C₁₀alkoxy, nonsubstituted or phenyl-substituted C₁˜C₁₀ straight- orbranched-chain alkenyl, C₃˜C₇ cycloalkyl or nonsubstituted orphenyl-substituted C₆˜C₁₂ aryl;

X and Y are, each independently, hydrogen, oxygen, hydroxy or sulfur;

Z¹, Z² and Z³ are carbon or nitrogen;

n is integer between 1˜10; and

‘

’ denotes single or double bond.

In a preferred embodiment,

A¹, A², A³ and A⁴ are, either independently or optionally, any oneselected from a group consisting of —H, halogen, C₁˜C₁₀ straight- orbranched-chain alkyl, —NR¹R², —NR¹(C═O)R², or two or more neighboringsubstituents A¹, A², A³ and A⁴ may form a ring together, wherein a ringformed by two or more neighboring substituents A¹, A², A³ and A⁴ mayinclude one or more hetero atom, and the hetero atom is N, O or S;

G is —OH, —O(C═O)R¹, —O(C═O) OR¹, —NR¹(C═O)R², —NR¹(C═O) OR² or

D¹, D², D³ and D⁴ are, either independently or optionally, any oneselected from a group consisting of halogen, C₁˜C₁₀ straight- orbranched-chain alkyl, —NR¹(C═O)R², —NR¹(C═O) OR² and —NR¹(C═O)—NR²R³, ortwo or more neighboring substituents D¹, D², D³ and D⁴ may form a ringtogether, wherein a ring formed by two or more neighboring substituentsD¹, D², D³ and D⁴ may include one or more hetero atom, and the heteroatom is N, O or S;

E is —H, —OH, —OR¹, —O(C═O)R¹, —O(C═O) OR¹, —O(C═O)NR¹R², —NR¹(C═O)R² or—NR¹(C═O)OR²;

R¹, R² and R³ are, each independently, hydrogen, nonsubstituted orphenyl-substituted C₁˜C₉ straight- or branched-chain alkyl,nonsubstituted or phenyl-substituted C₁˜C₅ straight- or branched-chainalkenyl or C₆˜C₁₀ aryl;

X and Y are, each independently, oxygen or hydroxy;

Z¹, Z² and Z³ are carbon;

n is integer between 15; and

‘

’ denotes single or double bond.

In a more preferred embodiment,

A¹, A², A³ and A⁴ are, either independently or optionally, any oneselected from a group consisting of —H, halogen and —NR¹R²;

G is —OH, —NR¹(C═O)R² or —NR¹(C═O)OR²;

D¹, D², D³ and D⁴ are, either independently or optionally, any oneselected from a group consisting of halogen, C₁˜C₁₀ straight- orbranched-chain alkyl and —NR¹(C═O)R²;

E is —H, —OH, —OR¹, —O(C═O)R¹, —O(C═O) OR¹ or —O(C═O)NR¹R²;

R¹, R² and R³ are, each independently, hydrogen, nonsubstituted orphenyl-substituted C₁˜C₈ straight- or branched-chain alkyl,nonsubstituted or phenyl-substituted C₁˜C₄ straight- or branched-chainalkenyl or C₆˜C₁₀ aryl;

X and Y are oxygen;

Z¹, Z² and Z³ are carbon;

n is integer between 13; and

‘

’ denotes double bond.

In a further more preferred embodiment,

A¹, A², A³ and A⁴ are, either independently or optionally, any oneselected from a group consisting of —H and —NR¹R²;

G is —NR¹(C═O)R²;

D¹, D², D³ and D⁴ are C₁˜C₁₀ straight- or branched-chain alkyl;

E is —O(C═O)R¹;

R¹, R² and R³ are, each independently, hydrogen or C₁˜C₇ straight- orbranched-chain alkyl;

X and Y are oxygen;

Z¹, Z² and Z³ are carbon;

n is integer between 13; and

‘

’ denotes double bond.

Concrete examples of the compound represented by Chemical Formula 1include:

-   1) Ethyl    2-(4-acetoxy-3-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-methoxyphenyl)acetate;-   2)    2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl    acetate;-   3) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-chlorophenyl    acetate;-   4)    6-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-2,3-dichlorophenyl    acetate;-   5)    2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,6-dichlorophenyl    acetate;-   6) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-ethylphenyl    acetate;-   7) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-methoxyphenyl    acetate;-   8) 4-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)biphenyl-3-yl    acetate;-   9) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-nitrophenyl    acetate;-   10) 3-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)biphenyl-4-yl    acetate;-   11) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-propylphenyl    acetate;-   12) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-ethylphenyl    acetate;-   13)    2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-sec-butylphenyl    acetate;-   14)    2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-tert-butylphenyl    acetate;-   15)    2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-tert-butylphenyl    acetate;-   16)    2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-3,4,5-trimethylphenyl    acetate;-   17)    2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-tert-pentylphenyl    acetate;-   18) Acetic acid    2-(2,3-diacetoxy-5-methyl-phenyl)-1,3-dioxo-indan-2-yl ester;-   19) Acetic acid    2-(2-acetoxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl ester;-   20) 2-(4-Acetyl-2-hydroxy-phenyl)-2-hydroxy-indan-1,3-dione;-   21)    2-(1,3-Dioxo-2-(propionyloxy)-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    propionate;-   22)    2-(2-(Butyryloxy)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    butyrate;-   23)    2-(2-Hydroxy-4-isopropylphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl    benzoate;-   24) 2-(2-Benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione;-   25) 2-(2-Benzyloxy-4-isopropyl-phenyl)-2-methoxy-indan-1,3-dione;-   26) 2-Hydroxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-indan-1,3-dione;-   27)    2-(2-Acetoxy-4-isopropylphenyl)-5-methoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl    acetate;-   28)    2-(2-Hydroxy-4-isopropylphenyl)-2-methoxy-1H-inden-1,3(2H)-dione;-   29)    2-(1,3-Dioxo-2-(pivaloyloxy)-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    pivalate;-   30)    2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    cinnamate;-   31) Dimethyl-carbamic acid    2-(2-dimethylcarbamoyloxy-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl    ester;-   32)    2-(2-(Acryloyloxy)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    acrylate;-   33) Diethyl-carbamic acid    2-(2-diethylcarbamoyloxy-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl    ester;-   34)    2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    diethylcarbamate;-   35)    2-Hydroxy-2-(4-hydroxy-2,5-dimethylphenyl)-1H-inden-1,3(2H)-dione;-   36) Acetic acid    2-(2-acetoxy-4-isopropyl-phenyl)-4-amino-1,3-dioxo-indan-2-yl ester;-   37) Acetic acid    2-(2-acetoxy-4-isopropyl-phenyl)-4-nitro-1,3-dioxo-indan-2-yl ester;-   38)    2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione;-   39)    2-Chloro-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione;-   40)    2-Azido-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione;-   41)    4-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;-   42)    N-(2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide;-   43)    N-(2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide;-   44)    N-(7-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide;-   45)    N-(5-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide;-   46)    4,7-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;-   47)    4,5-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;-   48) Methyl    2-(4-isopropyl-2(methoxycarbonyloxy)phenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl    carbamate;-   49)    2-(1,3-Dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    pentanoate;-   50)    2-(2-Isobutylamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    isobutyrate;-   51)    2-Hydroxy-2-(2-hydroxy-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-one;-   52) 2-Azido-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;-   53) 2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;-   54)    N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetamide;-   55)    N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)benzamide;-   56)    N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)    cyclopropancarboxamide;-   57) 2-(2-(Methylthio)phenyl)-2H-inden-1,3-dione;-   58) 2-(4-(Methylthio)phenyl)-2H-inden-1,3-dione;-   59) Methyl    2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate;-   60)    1-Ethyl-3-(2,3-dihydro-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-1H-inden-2-yl)urea;-   61)    1-(2,3-Dihydro-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-1H-inden-2-yl)urea;-   62) Isopropyl    2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate;-   63)    1-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-3-methoxy    urea;-   64) Ethyl    2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate;-   65)    N-(2-Bromo-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide;-   66)    N-(2-Amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide;-   67)    N,N′-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2,4-diyl)diacetamide;-   68)    2-(1,3-Dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    propionate;-   69)    2-(1,3-Dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    pentanoate;-   70)    2-(2-Benzamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    benzoate;-   71)    2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-methylpyridin-3-yl    acetate;-   72)    2-Hydroxy-2-(4-hydroxy-5-methylpyridin-3-yl)-1H-inden-1,3(2H)-dione;-   73)    2-(5-Chloro-3-hydroxypyridin-2-yl)-2-hydroxy-1H-inden-1,3(2H)-dione;-   74) 2-2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl;-   75) 2-Hydroxy-2-(6-hydroxyquinolin-7-yl)-1H-inden-1,3(2H)-dione;-   76) Butyric acid    2-(2-butyrylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester;-   77) Octanoic acid    7-isopropyl-9b-octanoylamino-10-oxo-9b,10-dihydro-5-oxa-indeno[2,1-a]inden-4b-yl    ester;-   78) Hexanoic acid    2-(2-hexanoylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester;-   79) Heptanoic acid    2-(2-heptanoylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester;-   80) 2,2-Dimethyl-propionic acid    2-(1,3-dioxo-2-pentanoylamino-indan-2-yl)-5-isopropyl-phenyl ester;-   81)    2-(4-Amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    pentanoate;-   82)    2-(4-Amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    hexanoate;-   83)    2-(4-Amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    heptanoate;-   84)    2-(4-Amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    propionate;-   85)    2-(4-Amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    butyrate;-   86)    N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)acetamide;-   87)    N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)propionamide;-   88)    N-(5-Ethyl-2-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)phenyl)acetamide;-   89)    N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)butyramide;-   90)    N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)isobutyramide;-   91)    2-(4-Amino-2-octanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    octanoate;-   92)    2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    methyl carbonate;-   93)    2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    pentanoate;-   94)    N-(2-(4-Acetamido-2-hydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)isobutyramide;-   95)    N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl)isobutyramide;-   96)    2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    butyl    carbonate2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    butyl carbonate;-   97)    2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    methylcarbamate;-   98) Dimethyl-carbamic acid    2-(2-acetylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester;-   99) Carbonic acid    2-(2-acetylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester    phenyl ester;-   100)    2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    dimethylcarbamate;-   101)    2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    ethyl carbonate;-   102) Ethyl    acetyl(2-(2-hydroxy-4-isopropylphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)carbamate;-   103)    2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl    ethylcarbamate;-   104) 2-(3-Methoxyphenyl)-2H-inden-1,3-dione;-   105) Ethyl    (6-(2-((ethoxycarbonyl)oxy)-4-isopropylphenyl)-5,7-dioxo-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)carbonate;-   106)    N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethoxyphenyl)isobutyramide;-   107)    N-[2-(4-Amino-2-hydroxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide;    and-   108)    N-[2-(2-Hydroxy-5,6-dimethoxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide.

Preferred examples of the 1,3-Dioxoindene derivative represented byChemical Formula 1 are as follows:

Compounds 27), 36)˜48), 53)˜56), 59)˜70), and 76)˜108).

More preferred examples of the 1,3-Dioxoindene derivative represented byChemical Formula include:

Compounds 6), 19), 21)˜23), 30), 32), 36), 48), 49), 68)˜70), 76),78)˜85), 92)˜97), and 99)˜103).

The 1,3-Dioxoindene derivatives, represented by Chemical Formula 1,according to the present invention may be used in the form ofpharmaceutical acceptable salts. Useful are acid addition salts formedwith pharmaceutically acceptable free acids. As used herein, the term“pharmaceutically acceptable salt” refers to any organic or inorganicsalt of the base compounds of Chemical Formula 1, not exhibiting a sideeffect in which the beneficial activity of the base compounds ofChemical Formula 1 is degraded when it is present at a concentrationcausing no toxicity and harm in the body. The free acids may beinorganic or organic. examples of useful inorganic free acids includehydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloricacid and phosphoric acid. As organic acids, citric acid, acetic acid,lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonicacid, gluconic acid, succinic acid, tartaric acid, galacturonic acid,embonic acid, glutamic acid, aspartic acid, oxalic acid, (D)- or(L)-malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid,4-toluenesulfonic acid, salicylic acid, benzoic acid, or malonic acidmay be used. The pharmaceutically acceptable salts may include alkalimetal salts (sodium salt, potassium salt, etc.) and alkaline earth metalsalts (calcium salt, magnesium salt, etc.). Acid addition salts usefulin the present invention include, but are not limited to, acetate,aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate,borate, camsylate, citrate, edisylate, esylate, formate, fumarate,gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate,trifluoroacetate, aluminum, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, alamine,potassium, sodium, tromethamine, and zinc salt, with hydrochloride ortrifluoroacetate being preferred. Addition salts according to thepresent invention may be prepared by typical methods. For example, theymay be prepared by dissolving the compound of Chemical Formula 1 in anorganic solvent, such as methanol, ethanol, acetone, methylene chloride,or acetonitrile, and adding an excess of organic acids or an excess ofaqueous inorganic acid solutions so as to precipitate or crystallizesalts. These addition salts may be obtained by precipitation orcrystallization, or by evaporating the solvent or excess acid and dryingor suction-filtering the precipitated salt.

Also, pharmaceutically acceptable metal salts formed with bases may fallwithin the range of pharmaceutically acceptable salts of the compound ofthe present invention. Examples of the metal salts useful in the presentinvention include alkali metal salts and alkaline earth metal salts. Byway of example, the compound of the present invention may be dissolvedin excess alkali metal hydroxide or alkaline earth metal hydroxide inwater, and, after the filtration of the solution to remove non-dissolvedcompound salts, the filtrate may be dried to afford the pharmaceuticallyacceptable salts of the compound of the present invention. Suitable foruse in pharmaceutics are sodium, potassium or calcium salts.Corresponding silver salts may be obtained by reacting the alkali metalor alkaline earth metal salts with suitable silver salt (e.g., silvernitrate).

Not only the 1,3-Dioxoindene derivatives of compound of Chemical Formula1 and pharmaceutically acceptable salts thereof, but also solvates,hydrates and isomers prepared therefrom, if having the same effect, arewithin the scope of the present invention.

Also, the present invention is concerned with a method for thepreparation of the 1,3-Dioxoindene derivative according to the presentinvention. In one embodiment, the method comprises acylating oralkylating the compound of Chemical Formula 2 with a base in a solventto afford a compound of Chemical Formula 1a (step 1), as illustrated inthe following Reaction Scheme 1:

wherein,

the compound of Chemical Formula 1a is a derivative of the compound ofChemical Formula 1, a pharmaceutically acceptable salt thereof, or anenantiomer thereof,

A¹, A², A³, A⁴, D¹, D², D³, D⁴, Z¹, Z², and Z³ are as defined inChemical Formula 1, respectively,

J and L are, independently or optionally, the same as A¹, A², A³, A⁴,D¹, D², D³, or D⁴

As the solvent useful in Reaction Scheme 1, diisopropylether,diethylether, dioxane, tetrahydrofurane (THF), dimethylformamide(DMF),dimethylacetamide(DMA), dimethylsulfoxide(DMSO), methylene chloride(MC),chlorobenzene, toluene, or benzene may be employed.

The base used in this reaction may be pyridine (PPTs), 4-dimethylaminopyridine, trimethylamine, or ethylamine.

In another embodiment, the method comprises:

reacting the compound of Chemical Formula 2 with thionyl chloride oroxalic chloride in the presence of a base in a solvent and then withammonia to give a compound of Chemical Formula 3 (step 1); and

acylating or alkylating the compound of Chemical Formula 3 in thepresence of a base in a solvent to afford a compound of Chemical Formula1b (step 2), as illustrated in the following Reaction Scheme 2:

wherein,

the compound of Chemical Formula 1b is a derivative of the compound ofChemical Formula 1, a pharmaceutically acceptable salt thereof, or anenantiomer thereof,

A¹, A², A³, A⁴, D¹, D², D³, D⁴, Z¹, Z², and Z³ are as defined inChemical Formula 1, respectively,

J and L are, independently or optionally, the same as A¹, A², A³, A⁴,D¹, D², D³, or D⁴

The solvents used in steps 1 and 2 in Reaction Scheme 2 of this methodmay be, independently, selected from the group consisting ofdiisopropylether, diethylether, dioxane, tetrahydrofurane(THF),dimethylformamide(DMF), dimethylacetamide(DMA), dimethylsulfoxide(DMSO),methylene chloride(MC), chlorobenzene, toluene, and benzene.

As the base for the acylating or alkylating reaction in this method,pyridine (PPTs), trimethylamine, ethylamine, or triphosgene may be used.

Also contemplated in accordance with an aspect of the present inventionis a pharmaceutical composition of the prevention or treatment of aviral disease, comprising an 1,3-Dioxoindene derivative represented byChemical Formula 1, a pharmaceutically acceptable salt thereof, or anenantiomer thereof as an active ingredient.

The viral disease that the pharmaceutical composition of the presentinvention targets is a disease caused by picornaviruses includingcoxsackie-, entero-, polio-, and rhinoviruses. Examples of the viraldisease include poliomyelitis, paralysis, acute hemorrhagicconjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesiculardisease, hepatitis A, myositis, myocarditis, pancreatitis, epidemicmyalgia, encephalitis, cold, herpangina, and foot-and-mouth disease.

Having excellent antiviral activity against picornaviruses such ascoxsackie-, entero-, echo-, polio- and rhinoviruses as well asexhibiting low cytotoxicity, the 1,3-Dioxoindene derivative of ChemicalFormula 1 can be useful as an active ingredient of a pharmaceuticalcomposition for the prevention or treatment of various viral diseasesincluding poliomyelitis, paralysis, acute hemorrhagic conjunctivitis,viral meningitis, hand-foot-and-mouth disease, vesicular disease,hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemicmyalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma,chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitismedia.

Clinically, the compound of the present invention may be administered inthe form of various formulations. For this, the compound is usuallyformulated in combination with a diluent or excipient, such as a filler,a thickening agent, a binder, a wetting agent, a disintegrant, asurfactant, etc.

Solid preparations intended for oral administration of the compound ofthe present invention may take the form of tablets, pills, powders,granules, capsules, troches, and the like. These solid preparations areformulated in combination with at least one excipient such as starch,calcium carbonate, sucrose, lactose, or gelatine. In addition to asimple excipient, a lubricant such as magnesium stearate, talc, or thelike may also be added. Liquid preparations intended for oraladministration include suspensions, internal use solutions, emulsion,syrups, and the like. In addition to a simple diluent such as water orliquid paraffin, various excipients, such as wetting agents, sweeteningagents, aromatics, preservatives, and the like may be contained in theliquid preparations for the oral administration of the compound of thepresent invention.

Also, the compound of the present invention may be in a parenteraldosage form such as sterile aqueous solutions, non-aqueous solvents,suspensions, emulsions, lyophilizates, suppositories, and the like.Propylene glycol, polyethylene glycol, vegetable oils such as olive oil,and esters such as ethyl oleate may be suitable for the non-aqueoussolvents and suspensions. The basic materials of suppositories includeWitepsol, macrogol, Tween 61, cacao butter, laurin butter, andglycerogelatin.

The compound of the present invention is administered in atherapeutically effective amount. The effective dose of the compound ofthe present invention varies depending on various factors including apatient's age, weight, sex, and health condition, the route ofadministration, and the severity of disease. Typically, the compound ofthe present invention may be administered at a daily dose of from 0.001to 100 mg/kg, and preferably at a daily dose of from 0.01 to 35 mg/kg.For an adult with a weight of 70 kg, the dose of the compound of thepresent invention may typically range from 0.07 to 7,000 mg/day, andpreferably from 0.7 to 2,500 mg/day. The formulations of the compoundmay be administered in a single dose or may be divided into multipledoses at regular intervals of time according to the instructions of aphysician or pharmacist who is responsible for monitoring or observingthe administration of the drug.

MODE FOR INVENTION

A better understanding of the present invention may be obtained throughthe following examples which are set forth to illustrate, but are not tobe construed as limiting the present invention.

<Example 1> Ethyl2-(4-acetoxy-3-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-methoxyphenyl)acetate

Ethyl2-(4b,9b-dihydroxy-6-methoxy-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-8-yl)acetate(0.50 g, 1.4 mmol) was completely dissolved in anhydrous dichloromethane(30 ml). This solution was added with anhydrous acetic acid (0.37 ml,3.9 mmol), pyridine (0.11 ml, 1.4 mmol), and 4-dimethyl aminopyridine(0.05 g), and stirred at room temperature for 3 hrs. After the reactionmixture was extracted with dichloromethane, the organic layer wasconcentrated and purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (0.03 g, 4%).

mp: 102-107° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.25 (t, J=7.2 Hz, 3H, CH3) 1.98 (s, 3H, OAc)2.19 (s, 3H, OAc) 3.60 (s, 2H, CH2) 3.73 (s, 3H OCH3) 4.12-4.19 (q,J=7.2, 14.4 Hz, 2H, CH2) 6.93 (s, 1H, ArH) 7.23 (s, 1H, ArH) 7.85-8.00(m, 4H, ArH). MS(EI): 454.

<Example2>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenylacetate

4b,9b-Dihydroxy-7,8-dimethyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(1.00 g, 3.5 mmol) was dissolved in anhydrous THF (50 ml). This solutionwas added with anhydrous acetic acid (0.67 ml, 7.1 mmol), pyridine (0.30ml, 3.5 mmol), and 4-dimethyl aminopyridine (0.1 g), and stirred at roomtemperature for 3 hrs. After the reaction mixture was extracted withdichloromethane, the organic layer was concentrated and purified usingcolumn chromatography (ethylacetate:hexane=1:4) to afford the titlecompound (0.55 g, 42%).

mp: 206-207° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.05 (s, 3H, CH₃) 2.19 (s, 3H, OAc) 2.23 (s,3H, OAc) 6.74 (s, 1H, ArH) 7.44 (s, 1H, ArH) 7.83-8.00 (m, 4H, ArH).MS(EI): 366.

<Example3>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-chlorophenylacetate

7-Chloro-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(2.00 g, 6.9 mmol) was completely dissolved in anhydrous THF (20 ml).This solution was added with anhydrous acetic acid (1.41 ml, 13.8 mmol),pyridine (0.55 ml, 6.9 mmol), and 4-dimethyl aminopyridine (0.2 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:3) to affordthe title compound (0.51 g, 19%).

mp: 148-150° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.04 (s, 3H, OAc) 2.20 (s, 3H, OAc) 7.04 (d,J=2.1 Hz, 1H, ArH) 7.30 (d, J=1.8 Hz, 1H, ArH) 7.68 (d, J=9.0 Hz, 1H,ArH) 7.89-7.93 (m, 2H, ArH) 7.99-8.03 (m, 2H, ArH). MS(EI): 372.

<Example4>6-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-2,3-dichlorophenylacetate

2-(3,4-Dichloro-2-hydroxyphenyl)-2-hydroyx-1H-inden-1,3(2H)-dione (2.00g, 6.9 mmol) was completely dissolved in anhydrous THF (20 ml). Thissolution was added with anhydrous acetic acid (1.41 ml, 13.8 mmol),pyridine (0.55 ml, 6.9 mmol), and 4-dimethyl aminopyridine (0.2 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4 to 1:2.5)to afford the title compound (0.037 g, 1.5%).

mp: 129-136° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.07 (s, 3H, OAc) 2.19 (s, 3H, OAc) 7.42 (d,J=8.8 Hz, 1H, ArH) 7.64 (d, J=8.7 Hz, 1H, ArH) 7.89-8.03 (m, 4H, ArH).MS(EI): 407.

<Example5>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,6-dichlorophenylacetate

2-(3,5-Dichloro-2-hycroxyphenyl)-2-hydroxy-1H-inden-1,3(2H)-dione (1.50g, 4.6 mmol) was completely dissolved in anhydrous THF (20 ml). Thissolution was added with anhydrous acetic acid (0.95 ml, 9.28 mmol),pyridine (0.37 ml, 4.6 mmol), and 4-dimethyl aminopyridine (0.15 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4) to affordthe title compound (80 g, 4.2%).

mp: 178-180° C.

¹H-NMR (200 MHz, CDCl₃) δ 2.07 (s, 3H, OAc) 2.20 (s, 3H, OAc) 7.48 (d,J=3.6 Hz, 1H, ArH) 7.72 (d, J=3.3 Hz, 1H, ArH) 7.92-8.08 (m, 4H, ArH).MS(EI): 407.

<Example6>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-ethylphenylacetate

7-Ethyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(2.00 g, 7.0 mmol) was completely dissolved in anhydrous THF (20 ml).This solution was added with anhydrous acetic acid (1.44 ml, 14.1 mmol),pyridine (0.56 ml, 7.0 mmol), and 4-dimethyl aminopyridine (0.2 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4) to affordthe title compound (2.28 g, 88%).

mp: 136-137° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (t, J=7.6 Hz, 3H, CH₃) 2.08 (s, 3H, OAc)2.19 (s, 3H, OAc) 2.57-2.64 (q, J=15.3 Hz, J=7.8 Hz, 2H, CH₂) 6.81 (s,1H, ArH) 7.11 (d, J=9.0 Hz, 1H, ArH) 7.59 (d, J=8.4 Hz, 1H, ArH)7.86-7.90 (m, 2H, ArH) 7.97-8.01 (m, 2H, ArH). MS(EI): 366.

<Example7>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-methoxyphenylacetate

4b,9b-Dihydroxy-8-methyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(3.03 g, 10.6 mmol) was dissolved in anhydrous THF (20 ml). Thissolution was added with anhydrous acetic acid (2.01 g, 21.3 mmol),pyridine (0.84 ml, 10.6 mmol), and 4-dimethyl aminopyridine (0.3 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:3 to 1:2.5)to afford the title compound (0.44 g, 11%).

mp: 184-186° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.15 (s, 3H, OAc) 2.17 (s, 3H, OAc) 3.78 (s,3H, OCH₃) 6.78 (d, J=8.7 Hz, 1H, ArH) 6.91 (dd, J=2.7, 9.0 Hz, 1H, ArH)7.12 (d, J=2.7 Hz, 1H, ArH) 7.60 (t, J=7.5 Hz, 1H, ArH) 7.76-7.85 (m,2H, ArH) 8.14 (d, J=7.8 Hz, 1H, ArH). MS(EI): 368.

<Example8>4-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)biphenyl-3-yl acetate

4b,9b-Dihydroxy-7-phenyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(2.00 g, 6.0 mmol) was dissolved in anhydrous THF (20 ml). This solutionwas added with anhydrous acetic acid (1.24 ml, 12.1 mmol), pyridine(0.48 ml, 6.0 mmol), and 4-dimethyl aminopyridine (0.2 g), and stirredat room temperature for 12 hrs. After the reaction mixture was extractedwith dichloromethane, the organic layer was concentrated and purifiedusing column chromatography (ethylacetate:hexane=1:4) to afford thetitle compound (0.41 g, 11%).

mp: 165-167° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.05 (s, 3H, OAc) 2.22 (s, 3H, OAc) 7.20 (s,1H, ArH) 7.33-7.43 (m, 3H, ArH) 7.51 (d, J=6.0 Hz, 3H, ArH) 7.78 (dd,J=8.4 Hz, J=1.8 Hz, 1H, ArH) 7.88-7.92 (m, 2H, ArH) 8.01-8.05 (m, 2H,ArH). MS(EI): 414.

<Example9>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-nitrophenylacetate

4b,9b-Dihydroxy-8-nitro-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(0.80 g, 2.6 mmol) was dissolved in anhydrous THF (20 ml). This solutionwas added with anhydrous acetic acid (0.54 ml, 5.3 mmol), pyridine (0.21ml, 2.6 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred atroom temperature for 30 hrs. After the reaction mixture was extractedwith dichloromethane, the organic layer was concentrated and purifiedusing column chromatography (ethylacetate:hexane=1:2 to 1:1) to affordthe title compound (0.44 g, 11%).

mp: 163-167° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.92 (s, 3H, OAc) 2.24 (s, 3H, OAc) 7.22 (d,J=9.0 Hz, 1H, ArH) 7.93-7.97 (m, 2H, ArH) 8.03-8.08 (m, 2H, ArH) 8.24(dd, J=8.4 Hz, J=3.0 Hz, 1H, ArH) 8.72 (d, J=2.7 Hz, 1H, ArH). MS(EI):383.

<Example10>3-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)biphenyl-4-ylacetate

4b,9b-Dihydroxy-8-phenyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(1.00 g, 3.0 mmol) was dissolved in anhydrous THF (20 ml). This solutionwas added with anhydrous acetic acid (0.62 ml, 6.0 mmol), pyridine (0.25ml, 3.0 mmol), and 4-dimethyl aminopyridine (0.1 g), and stirred at roomtemperature for 30 hrs. After the reaction mixture was extracted withdichloromethane, the organic layer was concentrated and purified usingcolumn chromatography (ethylacetate:hexane=1:4) to afford the titlecompound (0.12 g, 6%).

mp: 196-198° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.08 (s, 3H, OAc) 2.22 (s, 3H, OAc) 7.06 (d,J=8.4 Hz, 1H, ArH) 7.35-7.48 (m, 3H, ArH) 7.54-7.58 (m, 3H, ArH)7.88-7.92 (m, 3H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 414.

<Example11>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-propylphenylacetate

4b,9b-Dihydroxy-8-propyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(0.80 g, 2.70 mmol) was dissolved in anhydrous THF (20 ml). Thissolution was added with anhydrous acetic acid (0.55 ml, 5.40 mmol),pyridine (0.21 ml, 2.7 mmol), and 4-dimethyl aminopyridine (0.08 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4) to affordthe title compound (0.85 g, 56%)

mp: 108-111° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.96 (t, J=8.0 Hz, 3H, CH₃) 1.55-1.70 (m, 2H,CH₂) 2.08 (s, 3H, OAc) 2.24 (s, 3H, OAc) 2.61 (t, J=8.4 Hz, 2H, CH₂)6.92 (d, J=8.2 Hz, 1H, ArH) 7.28 (s, 1H, ArH) 7.55 (m, 1H, ArH)7.78-8.07 (m, 4H, ArH). MS(EI): 380.

<Example12>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-ethylphenylacetate

8-Ethyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(0.80 g, 2.70 mmol) was completely dissolved in anhydrous THF (20 ml).This solution was added with anhydrous acetic acid (0.57 ml, 5.66 mmol),pyridine (0.22 ml, 2.83 mmol), and 4-dimethyl aminopyridine (0.08 g),and stirred at room temperature for 12 hrs. After the reaction mixturewas extracted with dichloromethane, the organic layer was concentratedand purified using column chromatography (ethylacetate:hexane=1:4 to1:2) to afford the title compound (0.56 g, 27%).

mp: 153-154° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.25 (t, J=7.2 Hz, 3H, CH₃) 2.16 (s, 3H, OAc)2.20 (s, 3H, OAc) 2.61-2.69 (q, J=15.0, 7.5 Hz, 2H, CH₂) 6.89 (d, J=8.4Hz, 1H, ArH) 7.20 (d, J=8.4 Hz, 1H, ArH) 7.53 (s, 1H, ArH) 7.86-7.90 (m,2H, ArH) 7.98-8.02 (m, 2H, ArH). MS(EI): 366.

<Example13>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-sec-butylphenylacetate

8-sec-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(0.58 g, 1.8 mmol) was completely dissolved in anhydrous THF (10 ml).This solution was added with anhydrous acetic acid (0.39 ml, 3.7 mmol),pyridine (0.15 ml, 1.8 mmol), and 4-dimethyl aminopyridine (0.06 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4 to 1:2) toafford the title compound (0.70 g, 48%).

mp: 118-120° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.82 (t, J=9.0 Hz, 3H, CH₃) 1.21 (d, J=6.9 Hz,3H, CH₃) 1.52-1.61 (m, 2H, CH₂) 2.06 (s, 3H, OAc) 2.21 (s, 3H, OAc)2.59-2.66 (m, 1H, CH) 6.90 (d, J=8.4 Hz, 1H, ArH) 7.20 (dd, J=2.1, 8.4Hz, 1H, ArH) 7.50 (d, J=1.8 Hz, 1H, ArH) 7.87-7.91 (m, 2H, ArH)7.98-8.03 (m, 2H, ArH). MS(EI): 394.

<Example14>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-tert-butylphenylacetate

8-tert-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(0.50 g, 1.6 mmol) was completely dissolved in anhydrous THF (10 ml).This solution was added with anhydrous acetic acid (0.32 ml, 3.7 mmol),pyridine (0.13 ml, 1.8 mmol), and 4-dimethyl aminopyridine (0.05 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4 to 1:2) toafford the title compound (0.44 g, 36%).

mp: 195-196° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.29 (s, 9H, CH₃) 2.14 (s, 3H, OAc) 2.18 (s,3H, OAc) 6.80 (d, J=8.7 Hz, 1H, ArH) 7.37-7.40 (dd, J=2.1, 8.7 Hz, 1H,ArH) 7.52-7.61 (m, 2H, ArH) 7.75-7.85 (m, 2H, ArH) 8.16 (d, J=8.1 Hz,1H, ArH). MS(EI): 394.

<Example15>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-tert-butylphenylacetate

7-sec-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(0.52 g, 1.67 mmol) was completely dissolved in anhydrous THF (20 ml).This solution was added with anhydrous acetic acid (0.34 g, 3.3 mmol),pyridine (0.13 g, 1.6 mmol), and 4-dimethyl aminopyridine (0.05 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4 to 1:2) toafford the title compound (0.53 g, 42%).

mp: 119-120° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.25 (s, 9H, CH₃) 2.04 (s, 3H, OAc) 2.10 (s,3H, OAc) 6.95 (d, J=2.1 Hz, 1H, ArH) 7.29 (dd, J=8.4, 2.1 Hz, 1H, ArH)7.60 (d, J=8.4 Hz, 1H, ArH) 7.84-7.90 (m, 2H, ArH) 7.97-8.02 (m, 2H,ArH). MS(EI): 394.

<Example16>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-3,4,5-trimethylphenylacetate

4b,9b-Dihydroxy-8-propyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(0.69 g, 2.33 mmol) was dissolved in anhydrous THF (20 ml). Thissolution was added with anhydrous acetic acid (0.48 ml, 4.66 mmol),pyridine (0.18 g, 2.33 mmol), and 4-dimethyl aminopyridine (0.07 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4 to 1:1) toafford the title compound (0.016 g, 2%).

mp: 238-242° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.05 (s, 6H, CH₃) 2.22 (s, 6H, OAc) 2.59 (s,3H, CH₃) 6.54 (s, 1H, ArH) 7.56 (t, J=7.5 Hz, 1H, ArH) 7.78 (t, J=7.5Hz, 2H, ArH) 7.94 (d, J=6.6 Hz, 1H, ArH). MS(EI): 380.

<Example17>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-tert-pentylphenylacetate

4b,9b-Dihydroxy-8-tert-pentyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one(0.80 g, 2.46 mmol) was dissolved in anhydrous THF (20 ml). Thissolution was added with anhydrous acetic acid (0.50 g, 4.93 mmol),pyridine (0.19 ml, 2.46 mmol), and 4-dimethyl aminopyridine (0.08 g),and stirred at room temperature for 12 hrs. After the reaction mixturewas extracted with dichloromethane, the organic layer was concentratedand purified using column chromatography (ethylacetate:hexane=1:3) toafford the title compound (0.71 g, 38%).

mp: 146-151° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.68 (t, J=7.5 Hz, 3H, CH₃) 1.26 (s, 6H, CH₃)1.56-1.66 (m, 2H, CH₂) 2.06 (s, 3H, OAc) 2.20 (s, 3H, OAc) 6.90 (d,J=8.7 Hz, 1H, ArH) 7.31 (dd, J=8.7 Hz, 2.7 Hz, 1H, ArH) 7.64 (d, J=2.4Hz, 1H, ArH) 7.86-7.91 (m, 2H, ArH) 7.98-8.02 (m, 2H, ArH). MS(EI)=408.

<Example 18> Acetic acid 2-(2,3-diacetoxy-5-methyl-phenyl)-1,3-dioxo-indan-2-yl ester

4b,6,9b-Trihydroxy-8-methyl-4b,9b-dihydro-5-oxa-indeno[1,2-a]-inden-10-one(0.50 g, 1.70 mmol) was dissolved in anhydrous THF (20 ml). Thissolution was added with anhydrous acetic acid (0.36 g, 3.5 mmol),pyridine (0.14 ml, 1.7 mmol), and 4-dimethyl aminopyridine (0.05 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:2) to affordthe title compound (0.47 g, 65%).

mp: 192-194° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.08 (s, 3H, OAc) 2.17 (s, 3H, OAc) 2.19 (s,3H, OAc) 2.35 (s, 3H, CH₃) 7.06 (s, 1H, ArH) 7.35 (s, 1H, ArH) 7.86-7.89(m, 2H, ArH) 7.98-8.01 (m, 2H, ArH). MS(EI): 410.

<Example 19> Acetic acid2-(2-acetoxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl ester

4b,9b-Dihydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]-inden-10-one(0.80 g, 2.70 mmol) was dissolved in anhydrous THF (100 ml). Thissolution was added with anhydrous acetic acid (11.46 g, 121.4 mmol),pyridine (4.9 g, 60.7 mmol), and 4-dimethyl aminopyridine (1.8 g), andstirred at room temperature for 12 hrs. After the reaction mixture wasextracted with dichloromethane, the organic layer was concentrated andpurified using column chromatography (ethylacetate:hexane=1:4) to affordthe title compound (19.0 g, 82%).

mp: 136-137° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (d, J=6.9 Hz, 6H, CH₃) 2.09 (s, 3H, OAc)2.20 (s, 3H, OAc) 2.83-2.88 (q, J=6.9 Hz, 1H, CH) 6.83 (d, J=1.6 Hz, 1H,ArH) 7.14 (dd, J=8.4 Hz, J=1.8 Hz, 1H, ArH) 7.59 (d, J=8.4 Hz, 1H, ArH)7.77-7.88 (m, 2H, ArH) 7.97-8.01 (m, 2H, ArH). MS(EI): 380.

<Example 20>2-(4-Acetyl-2-hydroxy-phenyl)-2-hydroxy-indan-1,3-dione

To a solution of ninhydrin (1.00 g, 5.61 mmol) in acetic acid (20 ml)was added 1-(3-hydroxy-phenyl)-ethanone (0.76 g, 5.61 mmol), followed byheating for 3 hrs at 110° C. The reaction mixture was diluted withmethylene chloride, extracted with 2N NaOH aqueous solution, and theconcentrated organic layer was purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (White, 1.32 g,79%).

mp: 177-180° C.

¹H-NMR (300 MHz, CDCl₃) δ 3.87 (s, 3H, CH₃) 7.07 (d, J=7.0 Hz, 1H, ArH)7.32 (d, J=7.9 Hz, 1H, ArH) 7.43 (d, J=8.1 Hz, 1H, ArH) 7.91-7.94 (q,J=5.7, 3.0 Hz, 2H, ArH) 8.06-8.08 (q, J=5.7, 3.0 Hz, 2H, ArH). MS(EI):296.

<Example21>2-(1,3-Dioxo-2-(propionyloxy)-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpropionate

2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37mmol) was completely dissolved in anhydrous THF (20 ml). This solutionwas added with propionyl chloride (0.62 g, 6.74 mmol), and triethylamine(0.41 g, 4.04 mmol), followed by heating 12 hrs under reflux. After thereaction mixture was concentrated, extracted with dichloromethane, andthe organic layer was concentrated and purified using columnchromatography (ethylacetate:hexane=1:4) to afford the title compound(White, 0.23 g, 17%).

mp: 123-125° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.10-1.19 (m, 12H, CH₃) 2.31-2.39 (q, J=15.0,7.5 Hz, 2H, CH₂) 2.46-2.54 (q, J=15.0, 7.5 Hz, 2H, CH₂) 2.80-2.89 (m,1H, CH) 6.82 (s, 1H, ArH) 7.14 (d, J=8.4 Hz, 1H, ArH) 7.61 (d, J=8.1 Hz,1H, ArH) 7.83-7.86 (m, 2H, ArH) 7.95-7.99 (m, 2H, ArH). MS(EI)=408.

<Example22>2-(2-(Butyryloxy)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutyrate

2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37mmol) was completely dissolved in anhydrous methylene chloride (20 ml).This solution was added with butyryl chloride (0.72 g, 6.74 mmol), andtriethylamine (0.41 g, 4.04 mmol), followed by heating 24 hrs underreflux. After the reaction mixture was concentrated, extracted withdichloromethane, and the organic layer was concentrated and purifiedusing column chromatography (ethylacetate:hexane=1:2) to afford thetitle compound (White, 0.20 g, 14%).

mp: 98-102° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.94-1.02 (m, 6H, CH₃) 1.17 (s, 3H, CH₃) 1.20(s, 3H, CH₃) 1.59-1.73 (m, 4H, CH₂) 2.29 (t, J=7.2 Hz, 2H, CH₂) 2.45 (t,J=7.5 Hz, 2H, CH₂) 2.81-2.90 (m, 1H, CH) 6.80 (s, 1H, ArH) 7.13 (dd,J=8.4 Hz, 1.4H, 1H, ArH) 7.60 (d, J=8.4 Hz, 1H, ArH) 7.85-7.89 (m, 2H,ArH) 7.96-8.01 (m, 2H, ArH). MS(EI): 436.

<Example23>2-(2-Hydroxy-4-isopropylphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylbenzoate

2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37mmol) was completely dissolved in anhydrous methylene chloride (20 ml).This solution was added with benzoyl chloride (0.94 g, 6.74 mmol),triethylamine (0.41 g, 4.04 mmol), and DMPA (0.01 g), followed byheating 24 hrs under reflux. After the reaction mixture wasconcentrated, extracted with dichloromethane, and the organic layer wasconcentrated and purified using column chromatography(ethylacetate:hexane=1:4) to afford the title compound (0.81 g, 14%)

mp: 117-119° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.19-1.28 (m, 6H, CH₃) 2.84-2.97 (m, 1H, CH)6.91-8.09 (m, 12H, ArH). MS(EI): 400.

<Example 24>2-(2-Benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione

4b,9b-dihydroxy-7-isopropyl-4b,9b-dihydroxy-5-oxa-indeno[2,1-a]inden-10-one(0.50 g, 1.68 mmol) was completely dissolved in anhydrous DMF (10 ml).This solution was added with potassium carbonate (0.46 g, 3.26 mmol) andbenzyl bromide (0.26 g, 1.51 mmol), and stirred at room temperature for13 hrs. The reaction mixture was washed with 1N NaOH, extracted withdichloromethane, and the concentrated organic layer was purified usingcolumn chromatography (ethylacetate:hexane=1:4) to afford the titlecompound (0.40 g, 61%).

mp: 197-199° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6.9 Hz, 6H, CH₃) 2.83-2.93 (m, 1H,CH) 3.04 (s, 1H, OH) 4.67 (s, 2H, OCH₂) 6.69 (s, 1H, ArH) 6.91 (d, J=7.5Hz, 2H, ArH) 6.99 (d, J=8.1 Hz, 1H, ArH) 7.11-7.23 (m, 3H, ArH)7.57-7.60 (m, 2H, ArH) 7.61-7.71 (m, 3H, ArH). MS(EI): 386.

<Example 25>2-(2-Benzyloxy-4-isopropyl-phenyl)-2-methoxy-indan-1,3-dione

2-(2-benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione (0.10 g,0.25 mmol) was completely dissolved in anhydrous DMF (2 ml). Thissolution was added with sodium hydride (0.007 g, 0.31 mmol) and methyliodide (0.04 g, 0.28 mmol), and stirred at room temperature for 13 hrs.The reaction mixture was extracted with dichloromethane, and theconcentrated organic layer was purified using column chromatography(ethylacetate:hexane=1:4) to afford the title compound (12 mg, 12%).

mp: 140-144° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6.9 Hz, 6H, CH₃) 2.82-2.92 (m, 1H,CH) 3.44 (s, 1H, OCH₃) 4.63 (s, 2H, OCH₂) 6.68 (s, 1H, ArH) 6.88 (d,J=7.8 Hz, 2H, ArH) 6.99 (d, J=8.1 Hz, 1H, ArH) 7.09-7.21 (m, 3H, ArH)7.54-7.58 (m, 2H, ArH) 7.63-7.70 (m, 3H, ArH). MS(EI): 400.

<Example 26>2-Hydroxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-indan-1,3-dione

Ninhydrin (1.00 g, 5.61 mmol) was dissolved in acetic acid (15 ml), andthis solution was heated for 13 hrs. The reaction mixture wasconcentrated, and extracted with dichloromethane, and then concentratedorganic layer was purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (0.31 g, 20%).

mp: 210-213° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.16 (s, 6H, CH₃) 3.27 (s, 1H, OH) 4.81 (s,1H, OH) 7.02 (s, 2H, ArH) 7.90-7.92 (m, 2H, ArH) 8.04-8.07 (m, 2H, ArH).MS(EI): 282.

<Example27>2-(2-Acetoxy-4-isopropylphenyl)-5-methoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-ylacetate

4b,9b-dihydroxy-7-isopropyl-2-methoxy-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one(0.30 g, 0.91 mmol) was completely dissolved in anhydrous THF (10 ml).This solution was added with anhydrous acetic acid (0.18 g, 1.82 mmol),pyridine (0.07 g, 0.91 mmol) and DMAP (0.03 g), and stirred at roomtemperature. The reaction mixture was concentrated, and extracted withethylacetate, and the concentrated organic layer was purified usingcolumn chromatography (ethylacetate:hexane=1:3) to afford the titlecompound (0.19 g, 51%).

mp: 146-148° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (dd, J=2.1, 6.9 Hz, 6H, CH₃) 2.13 (s, 3H,OAc) 2.18 (s, 3H, OAc) 2.81-2.90 (m, 1H, CH) 3.93 (s, 3H, OCH₃) 6.84 (s,1H, ArH) 7.13 (d, J=1.2 Hz, 8.4 Hz, 1H, ArH) 7.33-7.36 (m, 2H, ArH) 7.57(d, J=8.4 Hz, 1H, ArH) 7.91 (d, J=6.0 Hz, 1H, ArH). MS(EI): 410.

<Example28>2-(2-Hydroxy-4-isopropylphenyl)-2-methoxy-1H-inden-1,3(2H)-dione

2-(2-(tert-butyldimethylsilyloxy)-4-isopropylphenyl)-2-methoxy-1H-indene-1,3(2H)-dione(0.2 g, 0.47 mmol) was completely dissolved in anhydrous THF (10 ml).This solution was added with quaternary ammonium fluoride (0.27 g, 1.04mmol), and stirred at room temperature for 1 hr. The reaction mixturewas concentrated, and extracted with ethylacetate, and the concentratedorganic layer was purified using column chromatography(ethylacetate:hexane=1:4) to afford the title compound (38 mg, 27%).

mp: 272-274° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.20 (d, J=7.2 Hz, 6H, CH₃) 2.82-2.91 (m, 1H,CH) 3.36 (s, 3H, OCH₃) 3.47 (s, 1H, OH) 6.59 (s, 1H, ArH) 6.94 (d, J=8.1Hz, 1H, ArH) 7.62 (d, J=8.1 Hz, 1H, ArH) 7.87-8.05 (m, 4H, ArH).MS(EI)=310.

<Example29>2-(1,3-Dioxo-2-(pivaloyloxy)-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpivalate

To a solution of4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one(1.00 g, 3.3 mmol) in anhydrous THF were added 2,2-dimethyl-propionylchloride (0.81 g, 6.7 mmol), trimethylamine (0.40 g, 4.0 mmol), and DMAP(0.1 g), followed by heating for 24 hrs under reflux. The reactionmixture was concentrated in a vacuum, and extracted with ethylaceteta.The extracted organic layer was purified using column chromatography(ethylacetate:hexane=1:6) to afford the title compound (0.38 g, 24%).

mp: 121-124° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (d, J=8.7 Hz, 6H, CH₃) 1.26 (s, 9H, CH₃)1.35 (s, 9H, CH₃) 6.67 (s, 1H, ArH) 7.07 (d, J=8.4 Hz, 1H, ArH) 7.42 (d,J=8.4 Hz, 1H, ArH) 7.79-7.83 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH).MS(EI): 464.

<Example30>2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylcinnamate

To a solution of4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one(1.00 g, 3.3 mmol) in anhydrous THF (10 ml) were added 3-phenyl-acyloylchloride (1.12 g, 6.7 mmol), trimethylamine (0.40 g, 4.0 mmol), and DMAP(0.1 g), followed by heating for 24 hrs under reflux. The reactionmixture was concentrated in a vacuum, and extracted with ethylacetate.The extracted organic layer was purified using column chromatography(ethylacetate:hexane=1:8 to 1:4) to afford the title compound (0.05 g,3.5%).

mp: 95-97° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.20 (dd, J=2.7 Hz, 6.8 Hz, 6H, CH₃) 2.86-2.91(m, 1H, CH) 4.20 (m, 1H, OH) 6.24 (d, J=16.0 Hz, 1H, CH) 6.49 (d, J=16.0Hz, 1H, CH) 6.93 (s, 1H, ArH) 7.20 (d, J=8.3 Hz, 1H, ArH) 7.35-7.59 (m,6H, ArH) 7.67-7.76 (m, 3H, ArH) 7.67-7.98 (m, 1H, ArH). MS(EI)=426.

<Example 31> Dimethyl-carbamic acid2-(2-dimethylcarbamoyloxy-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

To a solution of4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one(1.00 g, 3.3 mmol) in anhydrous THF (10 ml) were added dimethylcarbamoylchloride (0.72 g, 6.7 mmol), trimethylamine (0.41 g, 4.0 mmol), and DMAP(0.1 g), followed by heating for 24 hrs under reflux. The reactionmixture was concentrated in a vacuum, and extracted with ethylacetate.The extracted organic layer was purified using column chromatography(ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.20 g,13%).

mp: 203-205° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (d, J=6.8 Hz, 6H, CH₃) 2.73 (s, 3H, NCH₃)2.83 (s, 3H, NCH₃) 2.93 (s, 3H, NCH₃) 3.08 (s, 3H, NCH₃) 6.78 (s, 1H,ArH) 7.12 (d, J=8.0 Hz, 1H, ArH) 7.59 (d, J=8.0 Hz, 1H, ArH) 7.79-7.82(m, 2H, ArH) 7.95-7.98 (m, 2H, ArH). MS(EI): 438.

<Example32>2-(2-(Acryloyloxy)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylacrylate

To a solution of4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one(1.00 g, 3.37 mmol) in anhydrous THF (10 ml) were added acyloyl chloride(0.61 g, 6.74 mmol), trimethylamine (0.41 g, 4.0 mmol), and DMAP (0.1g), followed by heating for 24 hrs under reflux. The reaction mixturewas concentrated in a vacuum, and extracted with ethylacetate. Theextracted organic layer was purified using column chromatography(ethylacetate:hexane=1:2 to 1:1) to afford the title compound (0.26 g,19%).

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (d, J=2.1 Hz, 7.2 Hz, 6H, CH₃) 2.81-2.87(m, 1H, CH) 5.94-6.24 (m, 4H, CH₂) 6.44-6.47 (m, 2H, CH) 6.87 (s, 1H,ArH) 7.15 (d, J=8.1 Hz, 1H, ArH) 7.58 (d, J=8.1 Hz, 1H, ArH) 7.83-7.86(m, 2H, ArH) 7.96-7.99 (m, 2H, ArH). MS(EI): 404

<Example 33> Diethyl-carbamic acid2-(2-diethylcarbamoyloxy-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

To a solution of4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one(1.00 g, 3.3 mmol) in anhydrous THF were added trimethylamine (0.40 g,4.0 mmol), diethylcarbamoyl chloride (0.91 g, 6.7 mmol), and DMAP (0.1g), followed by heating for 24 hrs under reflux. The reaction mixturewas concentrated in a vacuum, and extracted with ethylacetate. Theextracted organic layer was purified using column chromatography(ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.54 g,32%).

mp: 103-105° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.02-1.28 (m, 18H, CH₃) 2.82-2.86 (m, 1H, CH)3.10-3.26 (m, 6H, NCH₂) 3.40 (q, J=14.2 Hz, 7.1 Hz, 2H, NCH₂) 6.73 (s,1H, ArH) 7.10 (d, J=8.3 Hz, 1H, ArH) 7.60 (d, J=8.3 Hz, 1H, ArH)7.76-7.79 (m, 2H, ArH) 7.93-7.96 (m, 2H, ArH). MS(EI): 494.

<Example34>2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyldiethylcarbamate

To a solution of4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one(1.00 g, 3.3 mmol) in anhydrous THF were added trimethylamine (0.40 g,4.0 mmol), diethylcarbamoyl chloride (0.91 g, 6.7 mmol), and DMAP (0.1g), followed by heating for 24 hrs under reflux. The reaction mixturewas concentrated in a vacuum, and extracted with ethylacetate. Theextracted organic layer was purified using column chromatography(ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.06 g,5%).

mp: 103-106° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.94-1.04 (m, 6H, CH₃) 1.20 (d, J=6.9 Hz, 6H,CH₃) 2.81-2.89 (m, 3H, CH, NCH₂) 3.08 (q, J=14.2 Hz, 7.1 Hz, 2H, NCH₂)4.03 (s, 1H, OH) 6.74 (s, 1H, ArH) 7.14 (d, J=8.1 Hz, 1H, ArH) 7.70 (d,J=7.8 Hz, 1H, ArH) 7.84-7.89 (m, 2H, ArH) 7.99-8.03 (m, 2H, ArH).MS(EI): 395

<Example35>2-Hydroxy-2-(4-hydroxy-2,5-dimethylphenyl)-1H-inden-1,3(2H)-dione

To a solution of ninhydrin (1.00 g, 5.6 mmol) in glacial acetic acid (20ml) was added 2,5-dimethyl phenol (0.68 g, 5.6 mmol), followed byheating for 24 hrs under reflux. The reaction mixture was concentratedin a vacuum, and extracted with ethylacetate. The concentrated organiclayer was purified using column chromatography (ethylacetate:hexane=1:6to 1:4) to afford the title compound (0.13 g, 8%).

mp: 228-230° C.

¹H-NMR (300 MHz, CDCl₃+CD₃OD) δ 2.12 (s, 3H, CH₃) 2.24 (s, 3H, CH₃) 3.39(s, 1H, OH) 5.59 (s, 1H, OH) 6.54 (s, 1H, ArH) 7.02 (s, 1H, ArH)7.90-7.93 (m, 2H, ArH) 8.03-8.06 (m, 2H, ArH). MS(EI)=282.

<Example 36> Acetic acid2-(2-acetoxy-4-isopropyl-phenyl)-4-amino-1,3-dioxo-indan-2-yl ester

Triethylamine (0.10 g, 0.6 mmol) was added to a solution of1-amino-4b,9b-dihydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one(0.20 g, 0.6 mmol) in methylene chloride (5 ml) at room temperature. Tothis reaction mixture, a dilution of 10% acetyl chloride (1 ml) inmethylene chloride was slowly added at 0° C. and stirred at roomtemperature 1 hr. The reaction mixture was concentrated in a vacuum, andextracted with ethylacetate. The concentrated organic layer was purifiedusing column chromatography (ethylacetate:hexane=1:4 to 1:2) to affordthe title compound (100 mg, 40%).

mp: 148-151° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (d, J=6.9 Hz, 6H, CH₃) 2.07 (s, 3H, OAc)2.18 (s, 3H, OAc) 2.83-2.88 (m, 1H, CH) 5.67 (s, 2H, NH₂) 6.83 (d, J=1.8Hz, 1H, ArH) 6.88 (d, J=8.4 Hz, 1H, ArH) 7.14 (dd, J=8.4 Hz, 2.1 Hz, 1H,ArH) 7.22 (d, J=7.2 Hz, 1H, ArH) 7.53 (t, J=7.2 Hz, 1H, ArH) 7.59 (d,J=8.4 Hz, 1H, ArH). 13C-NMR (300 MHz, DMSO) δ 19.86, 20.83, 23.98,34.89, 82.49, 111.47, 122.19, 122.52, 123.17, 123.91, 125.54, 130.59,138.55, 141.87, 148.87, 149.94, 153.17, 17.077, 171.10, 195.88, 196.68.MS(EI): 395.

<Example 37> Acetic acid2-(2-acetoxy-4-isopropyl-phenyl)-4-nitro-1,3-dioxo-indan-2-yl ester

Triethylamine (0.11 g, 1.16 mmol) was added to a solution of4b,9b-dihydroxy-7-isopropyl-1-nitro-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one(0.20 g, 0.58 mmol) in anhydrous chloroform (10 ml) at room temperature.To this reaction mixture, acetyl chloride (1 ml) was slowly added at 0°C. and stirred at room temperature 1 hr. The reaction mixture wasconcentrated in a vacuum, and extracted with ethylacetate. Theconcentrated organic layer was purified using column chromatography(ethylacetate:hexane=1:4 to 1:2) to afford the title compound (30 mg,12%).

mp: 94-98° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.20 (dd, J=6.9 Hz, 6H, CH₃) 2.19 (s, 3H, OAc)2.27 (s, 3H, OAc) 2.83-2.92 (m, 1H, CH) 6.91 (s, 1H, ArH) 7.15 (dd,J=8.2 Hz, 1.7 Hz, 1H, ArH) 7.53 (d, J=8.2 Hz, 1H, ArH) 7.99 (t, J=7.8Hz, 1H, ArH) 8.23 (dd, J=3.0 Hz, 7.8 Hz, 2H, ArH). ¹³C-NMR (300 MHz,CDCl₃) δ 19.72, 20.92, 23.45, 33.71, 82.07, 119.57, 12.83, 125.03,127.88, 129.86, 130.24, 131.48, 136.49, 141.09, 145.18, 148.77, 153.02,168.90, 169.92, 187.91, 190.47. MS(EI): 425.

<Example38>2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione

A solution of 4-nitro-2,3-dihydro-1H-inden-1-one (4.00 g, 20.9 mmol) in1,4-dioxane (40 ml) and glacial acetic acid (4 ml) was added withselenium dioxide (5.10 g, 46.03 mmol), and refluxed for 3 hrs. Afterfiltration at high temperature, the filtrate was concentrated to afford2,2-dihydroxy-4-nitro-2H-inden-1,3-dione (4.67 g, 100%). To a solutionof 2,2-dihydoxy-4-nitro-2H-inden-1,3-dione (4.67 g, 20.9 mmol) in TFA(10 ml) was added isopropyl anisole (3.14 g, 20.9 mmol), followed bystirring at 60° C. for 6 hrs. The reaction mixture was concentrated in avacuum, and extracted with aq. sodium bicarbonate and ethylacetate. Theconcentrated organic layer was purified using column chromatography(ethylacetate:hexane=1:4) to afford the title compound (1.19 mg, 16%).

¹H-NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6.9 Hz, 6H, CH₃) 2.82-2.92 (m, H,CH) 3.05 (s, 3H, OCH₃) 3.75 (s, 3H, OH) 6.60 (s, 1H, ArH) 6.96 (dd,J=7.8 Hz, 1H, ArH) 7.65 (d, J=8.1 Hz, 1H, ArH) 8.01 (t, J=7.8 Hz, 1H,ArH) 8.20-8.26 (m, 2H, ArH). MS(EI): 355.3.

<Example39>2-Chloro-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione

2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione(1.00 g, 2.8 mmol) was dissolved in excess of thionyl chloride (10 ml),stirred at room temperature for 2 hrs. The reaction mixture wasconcentrated in a vacuum, and extracted with aq. sodium bicarbonate andethylacetate. The organic layer was concentrated to afford the titlecompound (1.05 g, 77%).

mp: 81-84° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.25 (d, J=6.9 Hz, 6H, CH₃) 2.87-2.96 (m, 1H,CH) 3.44 (s, 3H, OCH₃) 6.65 (s, 1H, ArH) 7.02 (dd, J=1.2 Hz, 7.8 Hz, 1H,ArH) 8.05-8.12 (m, 1H, ArH) 8.22 (dd, J=1.2 Hz, 7.8 Hz, 1H, ArH)8.28-8.35 (m, 2H, ArH). MS(EI): 373.

<Example40>2-Azido-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione

2-chloro-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione(1.23 g, 3.2 mmol) was completely dissolved in acetone (30 ml). Thissolution was added with sodium azide (0.47 g, 7.2 mmol), sodium iodide(0.59 g, 3.9 mmol), water (6 ml), followed by heating 12 hrs underreflux. The reaction mixture was concentrated, and extracted withethylacetate, and the concentrated organic layer was purified usingcolumn chromatography (ethylacetate:hexane=1:4) to afford the titlecompound (Brown syrup, 600 mg, 48%).

¹H-NMR (300 MHz, CDCl₃) δ 1.23 (d, J=6.9 Hz, 6H, CH₃) 2.28-2.94 (m, 1H,CH) 3.40 (s, 3H, OCH₃) 6.63 (d, J=1.5 Hz, 1H, ArH) 7.01 (dd, J=1.5 Hz,8.1 Hz, 1H, ArH) 7.56-7.60 (m, 2H, ArH) 7.78-7.90 (m, 2H, ArH). MS(EI):380.

<Example41>4-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (52mg, 1.4 mmol) was completely dissolved in anhydrous ethanol (10 ml).This solution was added with iron (0.59 g, 10.6 mmol), conc. HCl (0.01ml) and water (1 ml). The reaction mixture was heated for 3 hrs underreflux. After filtration at high temperature to remove iron, thefiltrate was concentrated in a vacuum and purified using columnchromatography(ethylacetate:hexane=1:2) to afford the title compound(0.32 g, 68%).

mp: 219-220° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6.9 Hz, 6H, CH₃) 2.82-2.91 (m, 1H,CH) 3.41-3.45 (s, 3H, OCH₃) 6.60 (d, J=1.2 Hz, 1H, ArH) 6.89-6.98 (m,2H, ArH) 7.21-7.27 (m, 1H, ArH) 7.56-7.66 (m, 2H, ArH). MS(EI): 325.

<Example 42>N-(2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide(1.50 g, 6.4 mmol) was completely dissolved in anhydrous dioxane (15ml). This solution was added with selenium oxide (1.56 g, 14.0 mmol) andAcOH (1.5 ml). The reaction mixture was heated for 12 hrs under reflux.After filtration at high temperature, the filtrate was concentrated toafford 1.79 g (100%). The resulting product was extracted with ethylacetate, and concentrated organic layer was purified using columnchromatography(ethylacetate:hexane=1:1) to afford the title compound(0.52 g, 20%).

mp: 110-115° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.23 (d, J=6.9 Hz, 6H, CH₃) 2.29 (s, 3H, CH₃),2.84-2.93 (m, 1H, CH) 3.57 (s, 3H, OCH₃), 3.78 (s, 1H, OH), 6.63 (s, 1H,ArH) 7.00 (dd, J=1.5, 8.1 Hz, 1H, ArH) 7.68 (d, J=8.1 Hz, 1H, ArH) 8.28(d, J=8.7 Hz, 1H, ArH) 9.04 (d, J=2.4, 9.0 Hz, 1H, ArH) 10.54 (s, 1H,NH). MS(EI): 412.39.

<Example 43>N-(2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

N-(2,2-dihydroxy-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide(2.60 g, 11.1 mmol) was completely dissolved in anhydrous dioxane (20ml). This solution was added with selenium oxide (2.70 g, 24.4 mmol) andAcOH (1.5 ml). The reaction mixture was heated for 7 hrs under reflux.After filtration at high temperature, the filtrate was concentrated toafford 1.79 g (100%). Trifluoroacetic solution of the resulting productwas added with isopropyl-3-methoxybenzene (1.66 g, 11.1 mmol), followedby stirring for 12 hrs. The remainder was extracted with ethyl acetate,and concentrated organic layer was purified using columnchromatography(ethylacetate 100%) to afford the title compound (0.64 g,14%).

mp: 199-201° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.23 (d, J=6.9 Hz, 6H, CH₃) 2.28 (s, 3H, CH₃),2.84-2.91 (m, 1H, CH) 3.42 (s, 3H, OCH₃), 3.77 (s, 1H, OH), 6.65 (s, 1H,ArH) 7.00 (dd, J=1.4, 7.9 Hz, 1H, ArH) 7.63 (d, J=7.9 Hz, 1H, ArH) 7.85(d, J=8.1 Hz, 1H, ArH) 8.35 (d, J=8.1 Hz, 1H, ArH) 9.79 (s, 1H, NH).MS(EI): 412.

<Example 44>N-(7-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide(0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3ml). This solution was added with iron (0.098 g), conc. HCl (0.05 ml)and water (0.3 ml). The reaction mixture was heated for 2 hrs underreflux. After filtration at high temperature to remove iron, thefiltrate was concentrated in a vacuum and purified using columnchromatography(ethylacetate:hexane=1:2) to afford the title compound (65mg, 71%).

¹H-NMR (300 MHz, CDCl₃) δ 1.22 (s, 6H, CH₃) 2.20 (s, 3H, CH₃) 2.83-2.92(m, 1H, CH) 3.50 (s, 3H, OCH₃) 3.78 (s, 1H, OH) 5.54 (s, 2H, NH₂) 6.66(d, J=2.7 Hz, 1H, ArH) 6.91-7.07 (m, 2H, ArH) 7.56 (d, J=7.8 Hz, 1H,ArH) 8.76 (d, J=3.3, 9.0 Hz, 1H, ArH) 9.81 (s, 1H, NH). MS(EI): 382.

<Example 45>N-(5-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide(0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3ml). This solution was added with iron (0.098 g), conc. HCl (0.05 ml)and water (0.3 ml). The reaction mixture was heated for 2 hrs underreflux. After filtration at high temperature to remove iron, thefiltrate was concentrated in a vacuum and purified using columnchromatography(ethylacetate 100%) to afford the title compound (90 mg,98%).

mp: 124-131° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6.9 Hz, 6H, CH₃) 2.30 (s, 3H, CH₃)2.83-2.92 (m, CH) 3.46 (s, 3H, OCH₃) 3.78 (s, 1H, OH) 5.36 (s, 2H, NH₂)6.62 (s, 1H, ArH) 6.93 (d, J=8.1 Hz, 1H, ArH) 7.14 (d, J=8.4 Hz, 1H,ArH) 7.56 (d, J=8.1 Hz, 1H, ArH) 7.70 (d, J=8.1 Hz, 1H, ArH) 9.56 (s,1H, NH). MS(EI): 382.

<Example46>4,7-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

N-(7-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide(45 mg, 0.10 mmol) was completely dissolved in 6M HCl (1.4 ml) andmethanol (0.1 ml), followed by heating for 90 min at 80 D. The reactionmixture was diluted with methylene chloride, extracted with 2N NaOHaqueous solution, and the concentrated organic layer was purified usingcolumn chromatography (ethylacetate:hexane=1:1) to afford the titlecompound (80 mg, 200%).

mp: 243-247° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6.9 Hz, 6H, CH₃) 2.84-2.88 (m, 1H,CH) 3.55 (s, 3H, OCH₃) 3.78 (s, 1H, OH) 5.20 (s, 2H, NH₂) 6.64 (s, 1H,ArH) 6.90 (s, 3H, ArH) 7.52 (d, J=7.8 Hz, 1H, ArH). MS(EI): 340.

<Example47>4,5-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

N-(5-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide(85 mg, 0.19 mmol) was completely dissolved in 6M HCl (1.4 ml) andmethanol (0.1 ml), followed by heating for 40 min at 80□. The reactionmixture was diluted with methylene chloride, extracted with 2N NaOHaqueous solution, and the concentrated organic layer was purified usingcolumn chromatography (ethylacetate:hexane=1:1) to afford the titlecompound (30 mg, 44%).

mp: 272-274° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6.9 Hz, 6H, CH₃) 2.83-2.92 (m, 1H,CH) 3.33 (s, 3H, OCH₃) 3.76 (s, 1H, OH) 4.13 (s, 2H, NH₂) 6.63 (s, 1H,ArH) 6.96 (d, J=7.8 Hz, 1H, ArH) 7.68 (d, J=7.8 Hz, 1H, ArH) 7.83 (d,J=8.1 Hz, 1H, ArH) 8.08 (d, J=8.4 Hz, 1H, ArH). MS(EI): 340.

<Example 48> Methyl2-(4-isopropyl-2(methoxycarbonyloxy)phenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate

9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one(0.30 g, 1.01 mmol) was completely dissolved in THF (10 ml). Thissolution was added with triethylamine (0.17 ml, 1.21 mmol) andmethylchloroformate (0.07 ml, 1.01 mmol), followed by heating for 3 hrsunder room temperature. After the reaction mixture was concentrated in avacuum, extracted with water and methylene chloride, and purified usingcolumn chromatography (ethylacetate:hexane=1:2) to afford the titlecompound (0.30 g, 72%).

mp: 105-107° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (d, J=6.9 Hz, 6H), 2.85 (q, J=7.1 Hz,1H), 3.61 (s, 3H), 3.89 (s, 3H), 5.97 (s, 1H), 6.91 (s, 1H), 7.14 (d,J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.82-7.87 (m, 2H), 7.97-8.03 (m,2H).

<Example49>2-(1,3-Dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpentanoate

9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one(0.30 g, 1.01 mmol) was dissolved in THF (10 ml). This solution wasadded with valeryl chloride (0.12 ml, 1.01 mmol), followed by heatingfor 1 hr under room temperature. After the reaction mixture wasconcentrated in a vacuum, extracted with water and methylene chloride,and purified using column chromatography (ethylacetate:hexane=1:4) toafford the title compound (0.10 g, 20%).

mp: 117-118° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.8 Hz, 3H), 1.00 (t, J=8.1 Hz,3H), 1.17 (d, J=6.8 Hz, 6H), 1.29-1.40 (m, 2H), 1.42-1.62 (m, 4H), 1.77(q, J=8.8 Hz, 2H), 2.24 (t, J=8.3 Hz, 2H), 2.65 (t, J=9.4 Hz, 2H), 2.84(q, J=7.8 Hz, 1H), 6.67 (s, 1H), 6.85 (s, 1H), 7.05 (dd, J=1.4 Hz, 8.3Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.79-7.84 (m, 2H), 7.93-7.99 (m, 2H).

<Example50>2-(2-Isobutylamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylisobutyrate

9b-Amino-4b-hydro-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]-inden-10-one(0.30 g, 1.01 mmol) was dissolved in THF (10 ml). This solution wasadded with triethylamine (0.17 ml, 1.21 mmol), isobutyryl chloride (0.10ml, 1.01 mmol), and stirred at room temperature for 1 hrs. The reactionmixture was concentrated in a vacuum, and extracted with water andmethylene chloride. The extracted organic layer was purified usingcolumn chromatography (ethylacetate:hexane=1:2) to afford the titlecompound (0.10 g, 23%).

mp: 195-197° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.15 (d, J=6.9 Hz, 6H), 1.17 (d, J=6.9 Hz,6H), 1.38 (d, J=7.0 Hz, 6H), 2.45 (q, J=7.3 Hz, 1H), 2.77-3.00 (m, 2H),6.70 (s, 1H), 6.82 (d, J=1.7 Hz, 1H), 7.04 (dd, J=1.7 Hz, 8.2 Hz, 1H),7.29 (d, J=8.2 Hz, 1H), 7.77-7.84 (m, 2H), 7.93-7.99 (m, 2H).

<Example51>2-Hydroxy-2-(2-hydroxy-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-one

To a solution of4b,9b-dihydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one(1.0 g, 3.3 mmol) in diethylene glycol (10 ml) were added with hydrazinehydrate (80%, 0.36 g, 9.6 mmol), followed by stirring at 150° C. for 15min. The reaction mixture was added potassium hydroxide (360 mg, 6.4mmol), and stirred at 165-170° C. for 1 hrs. The reaction mixture wasextracted with ethylacetate, and purified using column chromatography(20% ethylacetate in hexane) to afford the title compound (60 g, 6.5%).

mp: 144-146° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.17 (d, J=7 Hz, 6H, CH₃) 2.75-2.79 (septet,1H, CH) 3.52-3.69 (m, 2H, CH₂) 6.57 (d, J=8.0 Hz, 1H, ArH) 6.70 (d,J=8.0 Hz, 1H, ArH) 6.79 (s, 1H, ArH) 7.41 (t, J=6.8 Hz, 2H, ArH) 7.65(t, J=7.1 Hz, 1H, ArH) 7.82 (d, J=7.7 Hz, 1H, ArH). MS(EI): 282.

<Example 52>2-Azido-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

To a solution of2-chloro-2-(4-isopropyl-2-methoxyphenyl)-1H-inden-1,3(2H)-dione (0.10 g,0.3 mmol) in acetone (5 ml) were added with sodium iodide (54 mg, 0.36mmol) and sodium azide (50 mg, 0.76 mmol) and distilled water (1 ml),followed by stirring at 80° C. for 6 hrs. The reaction mixture was addedwater, and extracted diethyl ether, and washed with water and brine inthat order. The washed organic layer was concentrated to afford thetitle compound (100 g, 98%).

mp: 175-177° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.24 (d, J=6.9 Hz, 6H, CH₃) 2.89 (septet,J=6.9 Hz, 1H, CH) 3.43 (s, 3H, OCH₃) 6.62 (d, J=1.2 Hz, 1H, ArH) 7.02(dd, J=7.8 Hz, J=1.2 Hz, 1H, ArH) 7.61 (d, J=8.1 Hz, 1H, ArH) 7.89-7.95(m, 2H, ArH) 8.03-8.09 (m, 2H, ArH). MS(EI): 335.

<Example 53>2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

To a solution of2-azido-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (50 mg, 0.15mmol) in methanol (10 ml) were added with triphenylphosphine (47 mg,0.18 mmol), followed by stirring at 60° C. for 4 hrs. The concentratedreaction mixture was purified using silica column chromatography (25%ethylacetate in hexane) to afford the title compound (25 g, 54%).

mp: 164-166° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.22 (d, J=6.9 Hz, 6H, CH₃) 2.88 (septet,J=6.9 Hz, 1H, CH) 3.30 (s, 3H, OCH₃) 6.57 (d, J=1.2 Hz, 1H, ArH) 6.97(dd, J=7.8 Hz, J=1.5 Hz, 1H, ArH) 7.60 (d, J=7.8 Hz, 1H, ArH) 7.86-7.90(m, 2H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 309.

<Example 54>N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetamide

2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.10 g, 0.32mmol) was dissolved in methylene chloride (4 ml). This solution wasadded with acetyl chloride (0.05 ml, 0.70 mmol), followed by stirring atroom temperature for 15 min, and added with triethylamine (0.12 ml, 0.86mmol), and stirred for 6 hrs. After the reaction mixture was extractedwith methylene chloride (50 ml×3), the organic layer was purified usingcolumn chromatography (45% ethylacetate in hexane) to afford the titlecompound (70 g, 62%).

mp: 222-224° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (d, J=6.9 Hz, 6H, CH₃) 1.95 (s, 3H, OAc)2.82 (septet, J=6.9 Hz, 1H, CH) 3.51 (s, 3H, OCH3) 6.63 (d, J=1.5 Hz,1H, ArH) 6.85-6.90 (m, 2H, NH, ArH) 7.41 (d, J=8.4 Hz, 1H, ArH)7.76-7.82 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH). MS(EI): 351.

<Example 55>N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)benzamide

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione(200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnighttogether with benzoyl chloride (0.09 mL, 0.77 mmol) and triethylamine(0.27 mL, 1.9 mmol) at room temperature. The reaction mixture wasextracted with dichloromethane, and purified by silica gel columnchromatography (30% ethylacetate in hexane) to afford the title compound(250 mg, 97%).

mp: 106-108° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6.9 Hz, 6H, CH₃) 2.86 (septet,J=6.9 Hz, 1H, CH) 3.64 (s, 3H, OCH₃) 6.72 (s, 1H, ArH) 6.90 (d, J=8.1Hz, 1H, ArH) 7.40-7.45 (m, 3H, ArH) 7.50-7.55 (m, 2H, ArH) 7.80-7.87 (m,4H, ArH) 8.01-8.06 (m, 2H, ArH). MS(EI): 413.

<Example 56>N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)cyclopropancarboxamide

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione(200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnighttogether with cyclopropyl carbonyl chloride (0.07 mL, 0.77 mmol) andtriethylamine (0.27 mL, 1.9 mmol) at room temperature. The reactionmixture was extracted with dichloromethane, and purified by silica gelcolumn chromatography (30% ethylacetate in hexane) to afford the titlecompound (235 mg, 96%).

mp: 145-147° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.22 (d, J=6.9 Hz, 6H, CH₃) 2.88 (septet,J=6.9 Hz, 1H, CH) 3.30 (s, 3H, OCH₃) 6.57 (d, J=1.2 Hz, 1H, ArH) 6.97(dd, J=7.8 Hz, J=1.5 Hz, 1H, ArH) 7.60 (d, J=7.8 Hz, 1H, ArH) 7.86-7.90(m, 2H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 377.

<Example 57>2-(2-(Methylthio)phenyl)-2H-inden-1,3-dione

Ninhydrin (0.10 g, 0.56 mmols) and thioanisole (0.07 mL, 0.56 mmols)were dissolved in trifluoroacetic acid (3 mL) and was stirred for 90 minat room temperature. The reaction mixture was neutralization with anaqueous sodium bicarbonate solution and was extracted with ethylacetateand was purified by silica gel column chromatography to afford the titlecompound (20 mg, 13%).

mp: 191-193° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.11 (s, 3H, SMe) 3.70 (b, 1H, OH) 7.34-7.42(m, 3H, ArH) 7.82 (m, 1H, ArH) 7.87-7.96 (m, 2H, ArH) 8.01-8.05 (m, 2H,ArH). MS(EI): 284.

<Example 58>2-(4-(Methylthio)phenyl)-2H-inden-1,3-dione

The title compound (115 mg, 77%) was obtained in a similar manner asdescribed in EXAMPLE 70.

mp: 153-155° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.14 (s, 3H, SMe) 3.74 (b, 1H, OH) 7.13-7.17(m, 2H, ArH) 7.26-7.31 (m, 2H, ArH) 7.90-7.95 (m, 2H, ArH) 8.03-8.06 (m,2H, ArH). MS(EI): 284.

<Example 59> Methyl2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione(0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.21g, 0.71 mmol) and stirred for 30 min. The reaction mixture wasconcentrated and was dissolved in methanol (6 mL) and was stirred for 2hrs and was concentrated to afford the title compound (220 mg, 93%).

mp: 153-155° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (d, J=6.9 Hz, 6H, CH₃) 2.83 (septet,J=6.9 Hz, 1H, CH) 3.50 (s, 3H, OCH₃) 3.65 (s, 3H, OCH₃) 5.94 (br, 1H,NH) 6.63 (d, J=1.5 Hz, 1H, ArH) 6.89 (dd, J=8.1 Hz, J=1.5 Hz, 1H, ArH)7.44 (d, J=8.1 Hz, 1H, ArH) 7.79-7.85 (m, 2H, ArH) 7.97-8.03 (m, 2H,ArH). MS(EI): 367.

<Example60>1-Ethyl-3-(2,3-dihydro-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-1H-inden-2-yl)urea

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione(0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.52g, 1.77 mmol) and stirred for 15 min. The reaction mixture wasconcentrated and was dissolved in anhydrous THF (10 ml) and was addedethylamine (2.0M in methanol, 2 mL, 400 mmol) and was stirred for 2 hrs.Concentrated reaction mixture was added dichloromethane to afford thetitle compound (450 mg, 74%).

mp: 267-269° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.17.1.23 (m, 9H, CH₃) 2.72 (br, 1H, NH) 2.89(septet, J=6.9 Hz, 1H, CH) 3.30-3.44 (m, 4H, CH₃ and CH₂) 3.50-3.62 (m,1H, CH2) 5.33 (s, 1H, NH) 6.70 (s, 1H, ArH) 6.96 (dd, J=8.1 Hz, J=1.2Hz, 1H, ArH) 7.51 (d, J=8.1 Hz, 1H, ArH) 7.59-7.64 (m, 1H, ArH)7.75-7.83 (m, 2H, ArH) 7.94 (d, J=7.8 Hz, 1H, ArH). MS(EI): 380.

<Example61>1-(2,3-Dihydro-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-1H-inden-2-yl)urea

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione(0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.52g, 1.77 mmol) and stirred for 15 min. The reaction mixture wasconcentrated and was dissolved in anhydrous THF (10 ml) and was addedammonia ((2.0M in IPA, 1.6 mL, 3.23 mmol) was stirred for 2 hrs. Thereaction mixture was concentrated and was purified using silica gelcolumn chromatography to afford the title compound (150 mg, 29%).

mp: 272-274° C.

¹H-NMR (300 MHz, Acetone-D₆) δ 1.24 (d, J=6.9 Hz, 6H, CH₃) 2.84-2.96 (m,3H, CH, NH₂) 3.30 (s, 3H, OMe) 6.81 (d, J=1.5 Hz, 1H, ArH) 6.91-6.95 (m,1.7H, ArH and NH) 7.18 (br, 0.63H, NH) 7.51 (d, J=7.8 Hz, 1H, ArH)7.59-7.64 (m, 1H, ArH) 7.79-7.86 (m, 3H, ArH). MS(EI): 352.

<Example 62> Isopropyl2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate

The title compound (150 mg, 23%) was obtained in a similar manner asdescribed in EXAMPLE 75.

mp: 159-161° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.10-1.17 (m, 12H, CH₃) 2.82 (septet, J=6.9Hz, 1H, CH) 3.48 (s, 3H, OMe) 4.76 (m, 1H, CH) 5.83 (s, 1H, NH) 6.62 (d,J=1.5 Hz, 1H, ArH) 6.88-6.93 (m, 1H, ArH) 7.45-7.49 (m, 1H, ArH)7.80-7.84 (m, 2H, ArH) 7.97-8.01 (m, 2H, ArH). MS(EI): 395.

<Example63>1-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-3-methoxyurea

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione(0.50 g, 1.61 mmol) in anhydrous THF (20 ml) was added triphosgene(0.528 g, 1.77 mmol) and stirred for 15 min. The reaction mixture wasconcentrated and was dissolved in anhydrous THF (20 ml) and was addedhydroxylamine hydrochloride(0.28 g, 4.04 mmol) was stirred for 2 hrs atroom temperature. The reaction mixture was concentrated and was purifiedusing silica gel column chromatography(1:1=ethylacetate:hexane) toafford the title compound (420 mg, 69%).

mp: 153-155° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.25 (dd, J=1.5 Hz, J=6.9 Hz, 6H, CH₃) 2.91(septet, J=6.9 Hz, 1H, CH) 2.97 (s, 1H, NH) 3.45 (s, 3H, OCH₃) 4.02 (s,3H, OCH₃) 5.51 (br, 1H, NH) 6.76 (d, J=1.5 Hz, 1H, ArH) 7.00 (dd, J=1.5Hz, J=7.8 Hz, 1H, ArH) 7.47 (d, J=7.8 Hz, 1H, ArH) 7.60-7.65 (m, 1H,ArH) 7.76-7.81 (m, 1H, ArH) 7.89-7.95 (t, J=8.4 Hz, 2H, ArH). MS(EI):382.

<Example 64> Ethyl2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione(0.80 g, 2.58 mmol) in anhydrous THF (20 ml) was added triphosgene (0.84g, 2.84 mmol) and stirred for 15 min. The reaction mixture wasconcentrated and was dissolved in ethanol (20 ml) was stirred for 2 hrsat room temperature to afford the title compound (0.95 g, 96%).

mp: 149-150° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.17-1.24 (m, 9H, CH₃) 2.83 (septet, J=6.9 Hz,1H, CH) 3.49 (s, 3H, OCH₃) 4.02 (q, 2H, CH₂) 5.89 (br, 1H, NH) 6.62 (s,1H, ArH) 6.89 (d, J=8.1 Hz, 1H, ArH) 7.46 (d, J=8.1 Hz, 1H, ArH)7.80-7.83 (m, 2H, ArH) 7.98-8.01 (m, 2H, ArH). MS(EI): 381.

<Example 65>N-(2-Bromo-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

A solution ofN-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-2,3-dihydro-1H-inden-4-yl)acetamide(0.25 g, 0.68 mmol) in dichloromethane (10 ml) and was added thionylbromide (0.08 mL, 1.02 mmol) and DMF (2 drops) was stirred for 2 hrs atroom temperature. The reaction mixture was extracted withdichloromethane and was purified using silica gel column chromatography(20% ethylacetate in hexane) to afford the title compound (0.22 g, 75%).

mp: 143-145° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.24 (d, J=6.9 Hz, 6H, CH₃) 2.63 (s, 3H, NAc)2.91 (septet, J=6.9 Hz, 1H, CH) 3.41 (s, 3H, OCH3) 6.61 (d, J=1.2 Hz,1H, ArH) 6.98 (dd, J=8.1 Hz, J=1.2 Hz, 1H, ArH) 7.70 (d, J=8.1 Hz, 1H,ArH) 7.81 (d, J=7.8 Hz, 1H, ArH) 7.86-7.91 (m, 1H, ArH) 9.00 (d, J=8.4Hz, 1H, ArH) 10.31 (br, 1H, NH). MS(EI): 430.2.

<Example 66>N-(2-Amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

A solution ofN-(2-azido-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-2,3-dihydro-1H-inden-4-yl)acetamide(115 mg, 0.29 mmol) in methanol (5 ml) and was added triphenylphosphine(92 mg, 0.35 mmol) and water (1 mL) was stirred for 2.5 hrs at 50° C.The reaction mixture was concentrated and purified using silica gelcolumn chromatography(30% ethylacetate in hexane, 1% triethylamine) toafford the title compound (75 mg, 70%).

mp: 183-185° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.23 (d, J=6.9 Hz, 6H, CH₃) 1.99 (br, 2H, NH₂)2.24 (s, 3H, NAc) 2.88 (septet, J=6.9 Hz, 1H, CH) 3.35 (s, 3H, OCH₃)6.59 (d, J=1.5 Hz, 1H, ArH) 6.98 (dd, J=7.8 Hz, J=1.5 Hz, 1H, ArH) 7.60(d, J=7.8 Hz, 1H, ArH) 7.66 (d, J=7.2 Hz, 1H, ArH) 7.84 (t, J=7.8 Hz,1H, ArH) 8.93 (d, J=8.1 Hz, 1H, ArH) 10.2 (br, 1H, NH). MS(EI): 366.

<Example 67>N,N′-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2,4-diyl)diacetamide

A solution ofN-(2-amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-2,3-dihydro-1H-inden-4-yl)acetamide(0.20 g, 0.54 mmol) in dichloromethane (10 mL) and was addedtriethylamine (0.23 mL, 1.6 mmol) and then stirred for overnight. Thereaction mixture was extracted with dichloromethane and purified usingsilica gel column chromatography(50% ethylacetate in hexane) to affordthe title compound (210 mg, 95%).

mp: 241-243° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (d, J=6.9 Hz, 6H, CH₃) 2.05 (s, 3H, NAc)2.23 (s, 3H, NAc) 2.85 (septet, J=6.9 Hz, 1H, CH) 3.55 (s, 3H, OCH3)6.65-6.74 (m, 2H, ArH and NH) 6.91 (dd, J=8.1 Hz, J=1.5 Hz, 1H, ArH)7.39 (d, J=8.1 Hz, 1H, ArH) 7.62 (d, J=7.5 Hz, 1H, ArH) 7.78 (t, J=8.1Hz, 1H, ArH) 8.86 (d, J=8.4 Hz, 1H, ArH) 10.1 (br, 1H, NH). MS(EI): 408.

<Example68>2-(1,3-Dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpropionate

A solution of9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one(0.10 g, 0.34 mmol) in dichloromethane (5 ml) was added triethylamine(0.14 mL, 1.02 mmol) and propionyl chloride(32.5 μL, 0.37 mmol) at 0° C.and then stirred for 4 hrs at room temperature. The reaction mixture wasextracted with dichloromethane and purified using silica gel columnchromatography(40% ethylacetate in hexane) to afford the title compound(116 mg, 85%).

mp: 173-175° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.07-1.19 (m, 9H, CH₃) 1.23-1.33 (m, 3H, CH₃)2.27 (q, J=7.5 Hz, 2H, CH₂) 2.68 (q, J=7.5 Hz, 2H, CH₂) 2.84 (septet,J=6.9 Hz, 1H, CH) 6.69 (s, 1H, NH) 6.86 (d, J=1.5 Hz, 1H, ArH) 7.06 (dd,J=1.5 Hz, J=8.1 Hz, 1H, ArH) 7.35 (d, J=8.1 Hz, 1H, ArH) 7.80-7.83 (m,2H, ArH) 7.95-7.98 (m, 2H, ArH). MS(EI): 407.

<Example69>2-(1,3-Dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpentanoate

A solution of9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one(0.15 g, 0.50 mmol) in dichloromethane (5 ml) was added triethylamine(0.21 mL, 1.52 mmol) and valeroyl chloride(74 μL, 0.61 mmol) at 0° C.and then stirred for overnight at room temperature. The reaction mixturewas extracted with dichloromethane and purified using silica gel columnchromatography(30% ethylacetate in hexane) to afford the title compound(150 mg, 68%).

mp: 128-130° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.2 Hz, 3H, CH₃) 0.99 (t, J=7.2 Hz,3H, CH₃) 1.18 (d, J=6.9 Hz, 6H, CH₃) 1.23-1.40 (m, 2H, CH₂) 1.42-1.62(m, 4H, CH₂) 1.72-1.82 (m, 2H, CH₂) 2.43 (t, J=7.5 Hz, 2H, CH₂) 2.65 (t,J=7.8 Hz, 2H, CH₂) 2.84 (septet, J=6.9 Hz, 1H, CH) 6.67 (s, 1H, NH) 6.85(d, J=1.5 Hz, 1H, ArH) 7.06 (dd, J=1.5 Hz, J=8.4 Hz, 1H, ArH) 7.34 (d,J=8.4 Hz, 1H, ArH) 7.79-7.84 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH).MS(EI): 463.

<Example70>2-(2-Benzamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbenzoate

A solution of9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one(0.25 g, 0.85 mmol) in dichloromethane (15 ml) was addeddiisopropylethylamine (0.73 mL, 4.22 mmol) and benzoyl chloride(0.29 mL,2.54 mmol) at 0° C. and then stirred for overnight at room temperature.The reaction mixture was extracted with dichloromethane and purifiedusing silica gel column chromatography (20% ethylacetate in hexane) toafford the title compound (280 mg, 66%).

mp: 138-140° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.22 (d, J=6.9 Hz, 6H, CH₃) 2.90 (septet,J=6.9 Hz, 1H, CH) 7.00 (d, J=1.5 Hz, 1H, ArH) 7.16 (dd, J=1.5 Hz, J=8.1Hz, 1H, ArH) 7.34-7.61 (m, 9H, ArH) 7.73-7.76 (m, 4H, ArH) 7.77-7.86 (m,2H, ArH) 8.10-8.12 (m, 2H, ArH). MS(EI): 503.

<Example71>2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-methylpyridin-3-ylacetate

The title compound was obtained in a similar manner as described inEXAMPLE 2.

¹H-NMR (200 MHz, CDCl₃): δ 8.33 (d, J=7.7 Hz, 1H), 7.80 (t, J=7.7 Hz,1H), 7.61 (t, J=7.6 Hz, 1H), 7.52-7.44 (m, 2H), 7.26 (d, J=8.0 Hz, 1H),2.59 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H).

<Example72>2-Hydroxy-2-(4-hydroxy-5-methylpyridin-3-yl)-1H-inden-1,3(2H)-dione

The title compound was obtained in a similar manner as described inEXAMPLE 24.

¹H-NMR (200 MHz, DMSO-d₆) δ 10.5 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.90(m, 2H), 7.65 (m, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H),2.51 (s, 3H).

<Example73>2-(5-Chloro-3-hydroxypyridin-2-yl)-2-hydroxy-1H-inden-1,3(2H)-dione

The title compound was obtained in a similar manner as described inEXAMPLE 24.

¹H-NMR (200 MHz, CDCl₃): δ 8.32 (d, J=7.9 Hz, 1H), 8.08 (m, 1H), 7.89(td, J=8.2, 1.2 Hz, 1H), 7.65 (t, J=7.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H),7.32 (d, J=1.4 Hz, 1H).

<Example 74>2-2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl

A solution of4b,9b-dihyroxy-7-methyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.25g, 0.85 mmol) in anhydrous dichloromethane (50 ml) was added anhydrousacetic acid (0.7 ml, 7.4 mmol), pyridine (0.3 ml, 3.7 mmol),4-dimethylaminopyridine (0.1 g) and then stirred for 3 hrs at roomtemperature. The reaction mixture was extracted with dichloromethane,the concentrated organic layer was purified using silica gel columnchromatography (ethylacetate:hexane=1:8) to afford the title compound(1.1 g, 84%).

m.p: 145-147° C.

¹H-NMR (300 MHz, CDCl₃): δ 2.07 (s, 3H, OAc), 2.19 (s, 3H, OAc), 2.31(s, 3H, CH₃), 6.80 (s, 1H, ArH), 7.08 (d, J=8.1 Hz, 1H, ArH), 7.57 (d,J=8.1 Hz, 1H, ArH), 7.86-8.02 (m, 4H, ArH). MS(EI): 352.

<Example 75>2-Hydroxy-2-(6-hydroxyquinolin-7-yl)-1H-inden-1, 3(2H)-dione

The title compound was obtained in a similar manner as described inEXAMPLE 24.

¹H-NMR (200 MHz, CDCl₃): δ 8.86 (d, J=8.5 Hz, 1H), 8.75 (m, 1H), 8.35(s, 1H), 8.05-7.88 (m, 3H), 7.75-7.55 (m, 3H), 7.36 (d, J=9.1 Hz, 1H),6.87 (s, 1H).

<Example 76> Butyric acid2-(2-butyrylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

A solution of9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one(0.20 g, 0.67 mmol) in anhydrous methylene chloride(10 ml) was addedtriethylamine (0.20 g, 2.01 mmol) and butyryl chloride (0.18 g, 1.69mmol) at room temperature and then stirred for 3 hrs. The reactionmixture was diluted in ethylacetate, and washed with water several time.The organic layer was dried, filtered, and purified using silica gelcolumn chromatography (ethylacetate:hexane=1:4 to 1:2) to afford thetitle compound (230 mg, 79%).

¹H-NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.5 Hz, 3H, CH₃) 1.08 (t, J=7.5 Hz,3H, CH₃) 1.18 (d, J=6.9 Hz, 6H, CH₃) 1.57-1.67 (m, 2H, CH₂) 1.78-1.86(m, 2H, CH₂) 2.23 (t, J=7.5 Hz, 2H, CH₂) 2.64 (t, J=7.5 Hz, 2H, CH₂)2.82-2.86 (m, 1H, CH) 6.61 (s, 1H, NH) 6.85 (d, J=1.5 Hz, 1H, ArH) 7.06(dd, J=1.5, 8.1 Hz, 1H, ArH) 7.33 (d, J=8.1 Hz, 1H, ArH) 7.80-7.85 (m,2H, ArH) 7.94-7.98 (m, 2H, ArH).

<Example 77> Octanoic acid7-isopropyl-9b-octanoylamino-10-oxo-9b,10-dihydro-5-oxa-indeno[2,1-a]inden-4b-ylester

A solution of9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one(0.20 g, 0.67 mmol) in anhydrous methylene chloride(10 ml) was addedtriethylamine (0.20 g, 2.01 mmol) and octanoyl chloride (0.27 g, 1.67mmol) and then stirred for 28 hrs. The reaction mixture was concentratedand extracted with ethylacetate. The concentrated organic layer waspurified using silica gel column chromatography (ethylacetate:hexane=1:6to 1:4) to afford the title compound as a syrup (55 mg, 15%).

¹H-NMR (300 MHz, CDCl₃) δ 0.88 (t, J=7.5 Hz, 3H, CH₃) 1.18 (d, J=6.9 Hz,6H, CH₃) 1.26-1.45 (m, 12H, CH₂) 1.54-1.65 (m, 4H, CH₂) 1.73-1.83 (m,2H, CH₂) 2.24 (t, J=7.8 Hz, 2H, CH₂) 2.34 (t, J=7.5 Hz, 2H, CH₂) 2.65(t, J=7.5 Hz, 2H, CH₂) 2.80-2.89 (m, 1H, CH) 6.61 (s, 1H, NH) 6.85 (d,J=1.5 Hz, 1H, ArH) 7.06 (dd, J=1.8, 8.4 Hz, 1H, ArH) 7.33 (d, J=8.4 Hz,1H, ArH) 7.79-7.84 (m, 2H, ArH) 7.94-7.99 (m, 2H, ArH).

<Example 78> Hexanoic acid2-(2-hexanoylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

A solution of9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one(0.20 g, 0.67 mmol) in anhydrous methylene chloride(10 ml) was addedtriethylamine (0.20 g, 2.01 mmol) and hexanoyl chloride(0.22 g, 1.69mmol) and then stirred for 5 hrs. The reaction mixture was concentratedand extracted with ethylacetate. The concentrated organic layer waspurified using silica gel column chromatography (ethylacetate:hexane=1:6to 1:4) to afford the title compound as a syrup (0.14 g, 46%).

¹H-NMR (300 MHz, CDCl₃) δ 0.88 (t, J=6.9 Hz, 3H, CH₃) 0.95 (t, J=6.9 Hz,3H, CH₃) 1.18 (d, J=6.9 Hz, 6H, CH₃) 1.25-1.37 (m, 6H, CH₂) 1.40-1.47(m, 2H, CH₂) 1.55-1.65 (m, 2H, CH₂) 1.74-1.84 (m, 2H, CH₂) 2.24 (t,J=7.5 Hz, 2H, CH₂) 2.65 (t, J=7.5 Hz, 2H, CH₂) 280-2.89 (m, 1H, CH) 6.60(s, 1H, NH) 6.85 (d, J=1.8 Hz, 1H, ArH) 7.05 (dd, J=1.8, 8.1 Hz, 1H,ArH) 7.33 (d, J=8.4 Hz, 1H, ArH) 7.80-7.84 (m, 2H, ArH) 7.93-7.98 (m,2H, ArH).

<Example 79> Heptanoic acid2-(2-heptanoylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

A solution of9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one(0.20 g, 0.67 mmol) in anhydrous methylene chloride(10 ml) was addedtriethylamine (0.20 g, 2.01 mmol) and heptanoyl chloride(0.25 g, 1.69mmol) and then stirred for 3 hrs. The reaction mixture was concentratedand extracted with ethylacetate. The concentrated organic layer waspurified using silica gel column chromatography (ethylacetate:hexane=1:6to 1:4) to afford the title compound as a syrup (0.21 g, 60%).

¹H-NMR (300 MHz, CDCl₃) δ 0.85-0.94 (m, 6H, CH₃) 1.18 (d, J=7.2 Hz, 6H,CH₃) 1.25-1.37 (m, 10H, CH₂) 1.54-1.63 (m, 4H, CH₂) 1.73-1.80 (m, 2H,CH₂) 2.24 (t, J=7.5 Hz, 2H, CH₂) 2.65 (t, J=7.5 Hz, 2H, CH₂) 2.82-2.86(m, 1H, CH) 6.60 (s, 1H, NH) 6.85 (d, J=1.5 Hz, 1H, ArH) 7.05 (dd,J=1.5, 8.4 Hz, 1H, ArH) 7.33 (d, J=8.1 Hz, 1H, ArH) 7.80-7.83 (m, 2H,ArH) 7.95-7.98 (m, 2H, ArH).

<Example 80>2,2-Dimethyl-propionic acid2-(1,3-dioxo-2-pentanoylamino-indan-2-yl)-5-isopropyl-phenyl ester

A solution of pentanoic acid[2-(2-hydroxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl]-amide (0.10 g,0.26 mmol) in anhydrous methylene chloride(10 ml) was addedtriethylamine (0.03 g, 0.31 mmol) and pivaloyl chloride(0.047 g, 0.39mmol) and then stirred for 2 hrs. The reaction mixture was concentratedand extracted with ethylacetate. The concentrated organic layer waspurified using silica gel column chromatography(ethylacetate:hexane=1:4) to afford the title compound (0.11 g, 91%).

¹H-NMR (300 MHz, CDCl₃) δ 0.88 (t, J=7.2 Hz, 3H, CH₃) 1.17 (d, J=6.9 Hz,6H, CH₃) 1.44-1.25 (m, 2H, CH₂) 1.50 (s, 9H, CH₃) 1.53-1.61 (m, 2H, CH₂)2.23 (t, J=7.2 Hz, 2H, ArH) 2.78-2.88 (m, 1H, CH) 6.77-6.79 (m, 2H, NH,ArH) 6.97 (d, J=1.2, 8.1 Hz, 1H, ArH) 7.08 (d, J=1.2, 8.1 Hz, 1H, ArH)7.79-7.82 (m, 2H, ArH) 7.95-7.98 (m, 2H, ArH).

<Example81>2-(4-amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpentanoate

Iron powder (0.03 g, 0.6 mmol), conc. HCl (0.05 ml), and water (0.5 ml)were added in that order to a solution of5-isopropyl-2-(4-nitro-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)phenyl pentanoate (43 mg, 0.08 mmol) in ethanol (5 ml). The reactionmixture was heated for 1 hrs under reflux. The reaction mixture was hotfiltered off, the filtrate was concentrated in a vacuum and purified bycolumn chromatography (ethylacetate:hexane=1:4 to 1:2) to afford thetitle compound (22 mg, 55%).

¹H-NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.2 Hz, 3H, CH₃) 0.98 (t, J=7.2 Hz,3H, CH₃) 1.16-1.61 (m, 12H, CH₂, CH₃) 1.73 (t, J=7.5 Hz, 2H, CH₂) 2.25(t, J=7.5 Hz, 2H, CH₂) 2.63 (t, J=8.1 Hz, 2H, CH₂) 2.80-2.89 (m, 1H, CH)5.69 (s, 2H, NH₂) 6.62 (s, 1H, NH) 6.77 (d, J=8.1 Hz, 1H, ArH) 6.85 (s,1H, ArH) 7.05 (d, J=6.9 Hz, 1H, ArH) 7.13 (d, J=6.9 Hz, 1H, ArH) 7.30(d, J=8.1 Hz, 1H, ArH) 7.40 (t, J=7.8 Hz, 1H, ArH).

<Example82>2-(4-Amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylhexanoate

Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml)were added in that order to a solution of2-(2-hexanamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylhexanoate (40 mg, 0.07 mmol) in ethanol (5 ml). The reaction mixture washeated for 1 hrs under reflux. The reaction mixture was hot filteredoff, the filtrate was concentrated in a vacuum and purified by columnchromatography (ethylacetate:hexane=1:4 to 1:2) to afford the titlecompound (21 mg, 57%).

¹H-NMR (300 MHz, CDCl₃) δ 0.79-0.96 (m, 6H, CH₃) 1.18 (dd, J=6.9 Hz, 6H,CH₃) 1.22-1.32 (m, 6H, CH₃) 1.36-1.41 (m, 2H, CH₂) 1.47-1.63 (m, 3H,CH₂) 1.73-1.82 (m, 1H, CH₂) 2.24 (t, J=7.5 Hz, 2H, CH₂) 2.65 (t, J=7.8Hz, 2H, CH₂) 2.80-2.89 (m, 1H, CH) 5.66 (s, 2H, NH2) 6.59 (s, 1H, NH)6.80 (d, J=8.1 Hz, 1H, ArH) 6.86 (d, J=1.8 Hz, 1H, ArH) 7.05 (dd, J=1.8,8.1 Hz, 1H, ArH) 7.15 (d, J=7.2 Hz, 1H, ArH) 7.30 (d, J=8.4 Hz, 1H, ArH)7.44 (d, J=7.8 Hz, 1H, ArH).

<Example83>2-(4-Amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylheptanoate

Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml)were added in that order to a solution of2-(2-heptanamido-4nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylheptanoate (60 mg, 0.10 mmol) in ethanol (5 ml). The reaction mixturewas heated for 1 hrs under reflux. The reaction mixture was hot filteredoff, the filtrate was concentrated in a vacuum and purified by columnchromatography (ethylacetate:hexane=1:6 to 1:4) to afford the titlecompound (20 mg, 36%).

¹H-NMR (300 MHz, CDCl₃) δ 0.79-0.97 (m, 6H, CH₃) 1.18 (dd, J=6.9 Hz, 6H,CH₃) 1.25-1.49 (m, 12H, CH₂) 1.58 (t, J=7.2 Hz, 2H, CH₂) 1.82 (t, J=7.2Hz, 2H, CH₂) 2.22 (t, J=7.5 Hz, 2H, CH₂) 2.65 (t, J=7.5 Hz, 2H, CH₂)2.80-2.89 (m, 1H, CH) 5.66 (s, 2H, NH₂) 6.59 (s, 1H, NH) 6.79 (d, J=8.1Hz, 1H, ArH) 6.85 (d, J=1.5 Hz, 1H, ArH) 7.05 (dd, J=1.8, 8.4 Hz, 1H,ArH) 7.15 (d, J=7.2 Hz, 1H, ArH) 7.29 (d, J=8.1 Hz, 1H, ArH) 7.42 (t,J=8.1 Hz, 1H, ArH).

<Example84>2-(4-Amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpropionate

Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml)were added in that order to a solution of5-isopropyl-2-(4-nitro-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)phenylpropionate (40 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixturewas heated for 1 hrs under reflux. The reaction mixture was hot filteredoff, the filtrate was concentrated in a vacuum and purified by columnchromatography (ethylacetate:hexane=1:4 to 1:2) to afford the titlecompound (28 mg, 75%).

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (dd, J=6.9 Hz, 6H, CH₃) 1.27 (dd, J=3.3,7.5 Hz, 6H, CH₃) 2.29 (q, J=7.5 Hz, 2H, CH₂) 2.70 (q, J=7.5 Hz, 2H, CH₂)2.80-2.89 (m, 1H, CH) 5.67 (s, 2H, NH₂) 6.60 (s, 1H, NH) 6.80 (d, J=8.1Hz, 1H, ArH) 6.87 (d, J=1.5 Hz, 1H, ArH) 7.06 (dd, J=1.5, 6.9 Hz, 1H,ArH) 7.16 (d, J=7.2 Hz, 1H, ArH) 7.32 (t, J=8.1 Hz, 1H, ArH) 7.43 (t,J=7.5 Hz, 1H, ArH).

<Example85>2-(4-Amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutyrate

Iron powder (0.07 g, 1.3 mmol), conc. HCl (0.05 ml), and water (1 ml)were added in that order to a solution of2-(2-butyramido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutyrate (90 mg, 0.18 mmol) in ethanol (5 ml). The reaction mixture washeated for 1 hrs under reflux. After filtration at high temperature, thefiltrate was concentrated in a vacuum and purified using columnchromatography(ethylacetate:hexane=1:4 to 1:2) to afford the titlecompound (70 mg, 83%).

¹H-NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.5 Hz, 3H, CH₃) 1.07 (t, J=7.5 Hz,3H, CH₃) 1.18 (d, J=6.9 Hz, 6H, CH₃) 1.64 (q, J=7.5, 14.7 Hz, 2H, CH₂)1.80 (q, J=7.5, 14.7 Hz, 2H, CH₂) 2.23 (t, J=7.5 Hz, 2H, CH₂) 2.64 (t,J=7.5 Hz, 2H, CH₂) 2.80-2.89 (m, 1H, CH) 5.70 (s, 2H, NH₂) 6.62 (s, 1H,NH) 6.74 (d, J=8.4 Hz, 1H, ArH) 6.86 (d, J=1.5 Hz, 1H, ArH) 7.05 (dd,J=1.5, 8.4 Hz, 1H, ArH) 7.12 (d, J=7.2 Hz, 1H, ArH) 7.28 (t, J=7.5 Hz,1H, ArH) 7.38 (t, J=7.5 Hz, 1H, ArH).

<Example 86> N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)acetamide

N-(3,4-dimethylphenyl)acetamide (915 mg, 5.62 mmol) and ninhydrin (1.00g, 5.62 mmol) were dissolved in conc. sulfuric acid (20 mL) and stirredat room temperature for 1.5 hrs. The reaction was stopped by slowingpouring the solution to 150 g of ice and stirring. The reaction mixturewas extracted with ethylacetate and water, washed with brine. The washedorganic layer was dried over sodium sulfate, concentrated in a vacuum,and purified through column chromatography (30% ethylacetate in hexane)to afford the title compound (yellow solid, 800 mg, 44%).

¹H-NMR (300 MHz, CDCl₃) δ 2.02 (s, 3H, NAc) 2.20 (s, 3H, CH₃) 2.22 (s,3H, CH₃) 6.11 (s, 1H, ArH) 7.03 (s, 1H, ArH) 7.99-8.02 (m, 2H, ArH)8.13-8.16 (m, 2H, ArH).

<Example 87>N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)propionamide

N-(3,4-dimethylphenyl)propion amide (500 mg, 2.82 mmol) and ninhydrin(500 mg, 2.82 mmol) were dissolved in conc. sulfuric acid (10 mL) andstirred at room temperature for 1.5 hrs. The reaction was stopped byslowing pouring the solution to 150 g of ice and stirring. The reactionmixture was extracted with ethylacetate and water, washed with brine.The washed organic layer was dried over sodium sulfate, concentrated ina vacuum, and purified through silica gel column chromatography (30%ethylacetate in hexane) to afford the title compound (yellow solid, 430mg, 45%).

¹H-NMR (300 MHz, DMSO) δ 1.26 (t, J=7.5 Hz, 3H, CH₃) 2.14 (s, 6H, CH₃)3.06-3.58 (m, 2H, CH₂) 6.84 (s, 1H, ArH/OH) 7.16 (s, 1H, ArH/OH) 7.48(s, 1H, ArH/OH) 7.56-7.61 (m, 1H, ArH) 7.70 (d, J=7.8 Hz, 1H, ArH)7.80-7.86 (m, 2H, ArH) 7.95-8.01 (m, 1H, ArH).

<Example 88>N-(5-Ethyl-2-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)phenyl)acetamide

N-(3-ethylphenyl)acetamide (500 mg, 3.06 mmol) and ninhydrin (546 mg,3.06 mmol) were dissolved in conc. sulfuric acid (10 mL) and stirred atroom temperature for 3 hrs. The reaction was stopped by slowing pouringthe solution to 150 g of ice and stirring. The reaction mixture wasextracted with ethylacetate and water, washed with brine. The washedorganic layer was dried over sodium sulfate, concentrated in a vacuum,and purified through silica gel column chromatography (30% ethylacetatein hexane) to afford the title compound (90 mg, 9%).

¹H-NMR (300 MHz, CDCl₃) δ 1.17 (t, J=7.5 Hz, 3H, CH₃) 2.45 (s, 3H, NAc)2.57 (q, J=7.5 Hz, 2H, CH₂) 6.30 (d, J=7.5 Hz, 1H, ArH) 6.81 (dd, J=7.5Hz, J=1.5 Hz, 1H, ArH) 7.09 (d, J=1.5 Hz, 1H, ArH) 7.98-8.03 (m, 2H,ArH) 8.11-8.15 (m, 2H, ArH).

<Example 89>N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)butyramide

N-(3,4-dimethylphenyl)butyramide (1.00 mg, 5.61 mmol) and ninhydrin(1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid (15 mL) andstirred at room temperature for 5 hrs. The reaction was stopped byslowing pouring the solution to 150 g of ice and stirring. The reactionmixture was extracted with ethylacetate and water, washed with brine.The washed organic layer was dried over sodium sulfate, concentrated ina vacuum, and purified through silica gel column chromatography (30%ethylacetate in hexane) to afford the title compound (yellow solid, 1.10g, 56%).

¹H-NMR (300 MHz, CDCl₃) δ 1.028 (t, J=7.5 Hz, 3H, CH₃) 1.69-1.79 (m, 2H,CH₂) 2.01 (s, 3H, CH₃) 2.17 (s, 3H, CH₃) 2.43 (t, J=7.5 Hz, 2H, CH₂)6.11 (s, 1H, ArH) 7.05 (s, 1H, ArH) 7.99-8.03 (m, 2H, ArH) 8.11-8.16 (m,2H, ArH).

<Example 90>N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)isobutyramide

N-(3,4-dimethylphenyl)isobutyramide (1.00 mg, 5.61 mmol) and ninhydrin(1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid (15 mL) andstirred at room temperature for 5 hrs. The reaction was stopped byslowing pouring the solution to 200 g of ice and stirring. The reactionmixture was extracted with ethylacetate and water, washed with brine.The washed organic layer was dried over sodium sulfate, concentrated ina vacuum, and purified through silica gel column chromatography (30%ethylacetate in hexane) to afford the title compound (yellow solid, 1.85g, 94%).

¹H-NMR (300 MHz, CDCl₃) δ 1.26 (d, J=6.9 Hz, 6H, CH₃) 2.01 (s, 3H, CH₃)2.18 (s, 3H, CH₃) 2.68 (sept, J=6.9 Hz, 1H, CH) 6.11 (s, 1H, ArH) 7.08(s, 1H, ArH) 7.99-8.03 (m, 2H, ArH) 8.11-8.16 (m, 2H, ArH).

<Example91>2-(4-Amino-2-octanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyloctanoate

Iron powder (58 mg, 1.03 mmol) and conc. HCl (3 drops) were added inthat order to a solution of5-isopropyl-2-(4-nitro-2-octanamino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)phenyloctanoate (80 mg, 0.14 mmol) in ethanol:water (9:1, 7 ml). The reactionmixture was heated for 3 hrs under reflux. After filtration at hightemperature, the filtrate was concentrated in a vacuum and purifiedusing silica gel column chromatography(20% ethylacetate in hexane, 1%triethylamine) to afford the title compound (45 mg, 59%).

¹H-NMR (300 MHz, CDCl₃) δ 0.84-0.88 (m, 6H, CH₃) 1.16-1.28 (m, 16H+6H,CH₂+CH₃) 1.51-1.64 (m, 4H, CH₂) 2.10-2.46 (m, 4H, CH₂) 2.85 (sept, J=6.9Hz, 1H, CH) 4.40 (br, 2H, NH₂) 5.98 (s, 1H, ArH/NH) 6.72 (s, 1H, ArH/NH)6.89-6.96 (m, 2H, ArH) 7.22-7.34 (m, 2H, ArH) 7.40-7.43 (m, 1H, ArH).

<Example92>2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylmethyl carbonate

Triethylamine (0.24 ml, 1.77 mmol) and methylchloroformate (0.11 ml,1.48 mmol) were added toN-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide(0.50 g, 1.48 mmol) in THF (5 ml). The reaction mixture was stirred atroom temperature for 12 hrs, concentrated in a vacuum to remove solvent.The reaction mixture was extracted with water and methylene chloride,and purified through silica gel column chromatography(ethylacetate:hexane=1:2) to afford the title compound (0.10 g, 14%).

¹H-NMR (300 MHz, CDCl₃) δ 1.17 (d, J=6.8 Hz, 6H), 1.89 (s, 3H), 2.84 (q,J=7.8 Hz, 1H), 3.89 (s, 3H), 6.90 (s, 1H), 7.01 (s, 1H), 7.10 (d, J=7.7Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.77-7.83 (m, 2H), 7.92-7.96 (m, 2H).

<Example93>2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpentanoate

Triethylamine (0.24 ml, 1.77 mmol) and Valeroyl chloride (0.18 ml, 1.48mmol) were added toN-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide(0.50 g, 1.48 mmol) in THF (10 ml). The reaction mixture was stirred atroom temperature for 12 hrs, concentrated in a vacuum to remove solvent.The reaction mixture was extracted with water and methylene chloride,and purified through silica gel column chromatography(ethylacetate:hexane=1:2) to afford the title compound (0.20 g, 32%).

¹H-NMR (300 MHz, CDCl₃) δ 0.99 (t, J=8.9 Hz, 3H), 1.17 (d, J=7.0 Hz,6H), 1.44-1.52 (m, 2H), 1.75 (q, J=8.3 Hz, 2H), 2.62 (t, J=8.9 Hz, 2H),2.83 (q, J=7.7 Hz, 1H), 6.81-6.87 (m, 2H), 7.06 (dd, J=1.3 Hz, 8.3 Hz,1H), 7.38 (d, J=7.7 Hz, 1H), 7.79-7.85 (m, 2H), 7.92-7.98 (m, 2H).

<Example 94>N-(2-(4-Acetamido-2-hydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)isobutyramide

N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide(0.20 g, 0.71 mmol) and N-(3,4-dimethylphenyl)isobutyramide (136 mg,0.71 mmol) were dissolved in conc. sulfuric acid (5 mL) and stirred atroom temperature for 3 hrs. The reaction mixture was extracted withethylacetate and ice-water, washed with brine. The washed organic layerdried over sodium sulfate, concentrated in a vacuum, and purifiedthrough silica gel column chromatography (30% ethylacetate in hexane) toafford the title compound (30 mg, 10%).

¹H-NMR (300 MHz, CDCl₃) δ 1.27 (d, J=6.9 Hz, 6H, CH₃) 2.08 (s, 3H, NAc)2.19 (s, 6H, CH₃) 2.69 (sept, J=6.9 Hz, 1H, CH) 6.30 (s, 1H, ArH), 7.02(d, J=9 Hz, 1H, ArH) 7.08 (s, 1H, ArH) 8.22 (d, J=9 Hz, 1H, ArH).

<Example 95> N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl)isobutyramide

Ninhydrin (0.5 g, 2.80 mmol) and N-(4-isopropylphenyl)acetamide (575 mg,2.80 mmol) were dissolved in conc. sulfuric acid (5-6 mL) and stirred atroom temperature for 15 hrs. The reaction mixture was extracted withethylacetate and ice-water, washed with brine. The washed organic layerwas dried over sodium sulfate, concentrated in a vacuum, and purifiedthrough silica gel column chromatography (20% ethylacetate in hexane) toafford the title compound (320 mg, 31%).

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (d, J=6.9 Hz, 6H, CH₃) 1.29 (d, J=6.9 Hz,6H, CH₃) 2.71 (sept, J=6.9 Hz, 1H, CH) 2.81 (sept, J=6.9 Hz, 1H, CH)6.31 (d, J=7.8 Hz, 1H, ArH) 6.83 (dd, J=1.5 Hz, J=7.8 Hz, 1H, ArH) 7.17(d, J=1.5 Hz, 1H, ArH) 7.98-8.02 (m, 2H, ArH) 8.11-8.15 (m, 2H, ArH).

<Example96>2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutylcarbonate2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutyl carbonate

9b-acetamido-7-isopropyl-1-nitro-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-4b-ylbutylcarbonate (0.11 g, 0.22 mmol) was completely dissolved in anhydrousethanol (5 ml). This solution was added with iron (0.09 g, 1.66 mmol),conc. HCl (0.05 ml) and water (0.5 ml). The reaction mixture was heatedfor 1.5 hrs under reflux. After filtration at high temperature to removeiron, the filtrate was concentrated in a vacuum and purified usingcolumn chromatography(ethylacetate:hexane=1:2) to afford the titlecompound (50 mg, 50%).

¹H-NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.2 Hz, 3H, CH₃) 1.22 (dd, J=7.2Hz, 16.8 Hz, 6H, CH₃) 1.33-1.44 (m, 2H, CH₂) 1.59-1.73 (m, 2H, CH₂) 1.95(s, 3H, CH₃) 2.04-2.90 (m, 1H, CH) 4.07-4.46 (m, 2H, OCH₂) 5.59 (s, 1H,NH) 6.10 (s, 1H, ArH) 6.60 (d, J=8.1 Hz, 1H, ArH) 6.75 (s, 1H, ArH) 6.91(dd, J=1.5, 7.8 Hz, 1H, ArH) 7.12 (d, J=7.2 Hz, 1H, ArH) 7.39-7.48 (m,1H, ArH).

<Example97>2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylmethylcarbamate

9b-chloro-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one(0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). Thissolution was added with methyl isocyanate (0.12 g, 2.22 mmol),trimethylamine (0.18 g, 1.77 mmol). The reaction mixture was heated for5 hrs under reflux. After concentrating in a vacuum to remove THF, andthe remainder was diluted with methylene chloride and washed with watermany times. After drying and filtrating, the organic layer was purifiedusing column chromatography(ethylacetate:hexane=1:2) to afford the titlecompound (0.25 g, 44%).

¹H-NMR (300 MHz, CDCl₃) δ 1.17 (d, J=6.9 Hz, 6H, CH₃) 2.01 (s, 3H, CH₃)2.79-2.91 (m, 4H, CH, CH₃) 5.22 (s, 1H, NH) 6.86 (s, 1H, NH) 6.95 (s,1H, ArH) 7.04 (d, J=7.8 Hz, 1H, ArH) 7.32 (d, J=8.4 Hz, 1H, ArH)7.80-7.83 (m, 2H, ArH) 7.94-7.97 (m, 2H, ArH).

<Example 98> Dimethyl-carbamic acid2-(2-acetylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-5-oxa-indeno[2,1-a]inden-9b-yl)-acetamide(0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). Thissolution was added with Dimethyl-carbamylchrolide (0.23 g, 2.22 mmol),Trimethylamine (0.17 g, 1.77 mmol). The reaction mixture was heated for24 hrs under reflux. After concentrating in a vacuum to remove THF, andthe remainder was diluted with Ethylacetate and washed with Bicarbonatesodium aqueous solution many times. After drying and filtrating, theorganic layer was purified using columnchromatography(ethylacetate:hexane=1:1) to afford the title compound(0.26 g, 43%).

¹H-NMR (300 MHz, CDCl₃) δ 1.17 (d, J=6.9 Hz, 6H, CH₃) 1.98 (s, 3H, CH₃)2.80-2.88 (sept, 1H, CH) 3.04 (s, 3H, CH₃) 3.23 (s, 3H, CH₃) 6.88 (s,1H, ArH) 7.01 (d, J=8.1 Hz, 1H, ArH) 7.16 (s, 1H, ArH) 7.23 (d, J=8.4Hz, 1H, ArH) 7.79-7.82 (m, 2H, ArH) 7.94-7.97 (m, 2H, ArH).

<Example 99> Carbonic acid2-(2-acetylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester phenylester

N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-5-oxa-indeno[2,1-a]inden-9b-yl)-acetamide(0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). Thissolution was added with Phenyl chroloformate (0.35 g, 2.22 mmol),Trimethylamine (0.18 g, 1.77 mmol). The reaction mixture was heated for24 hrs under reflux. After concentrating in a vacuum to remove THF, andthe remainder was diluted with Ethylacetate and washed with Bicarbonatesodium aqueous solution many times. After drying and filtrating, theorganic layer was purified using columnchromatography(ethylacetate:hexane=1:1) to afford the title compound(0.18 g, 26%).

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (d, J=6.9 Hz, 6H, CH₃) 2.04 (s, 3H, CH₃)2.82-2.91 (sept, 1H, CH) 6.67 (s, 1H, NH) 7.03 (s, 1H, ArH) 7.15 (d,J=8.4 Hz, 1H, ArH) 7.30-7.34 (m, 1H, ArH) 7.45-7.47 (m, 5H, ArH)7.81-7.84 (m, 2H, ArH) 8.00-8.02 (m, 2H, ArH).

<Example100>2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyldimethylcarbamate

2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyldimethylcarbamate (0.20 g, 0.4 mmol) was dissolved in anhydrous ethanol(10 ml) and water (1 ml). This solution was added with iron (0.18 g, 3.2mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 hrsunder reflux. After filtrating and washing with MeOH, the remainder wasconcentrated in a vacuum and purified using columnchromatography(ethylacetate:hexane=1:2) to afford the title compound (90mg, 50%).

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (d, J=6.9 Hz, 6H, CH₃) 1.98 (s, 3H, CH₃)2.97 (s, 3H, CH₃) 2.79-2.89 (m, 1H, CH) 3.05 (s, 3H, CH₃) 3.23 (s, 3H,CH₃) 5.67 (s, 2H, NH₂) 6.81 (d, J=8.1 Hz, 1H, ArH) 6.85 (s, 1H, NH) 7.01(d, J=8.4 Hz, 1H, ArH) 7.08 (s, 1H, ArH) 7.13-7.21 (m, 2H, ArH) 7.44 (t,J=8.1 Hz, 1H, ArH).

<Example 101>2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethyl carbonate

9b-chrolo-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one(0.70 g, 2.07 mmol) was dissolved in anhydrous THF (15 ml). Thissolution was added with Ethyl chroloformate (0.32 g, 3.11 mmol) andTrimethylamine (0.25 g, 2.48 mmol). The reaction mixture was stirred for4 hrs. After concentrating in a vacuum to remove THF, and the remainderwas diluted with Methylene chloride and washed with water many times.After drying and filtrating, the organic layer was purified using columnchromatography(ethylacetate:hexane=1:4) to afford the title compound (30mg, 3.6%).

¹H-NMR (300 MHz, CDCl₃) δ 1.16-1.28 (m, 9H, CH₃) 2.33 (s, 3H, CH₃)2.79-2.88 (m, 1H, CH) 4.02-4.15 (m, 2H, OCH₂) 5.90 (s, 1H, NH) 6.68 (s,1H, ArH) 7.07 (dd, J=1.5, 8.3 Hz, 1H, ArH) 7.42 (d, J=8.3 Hz, 1H, ArH)7.81-7.90 (m, 2H, ArH) 7.96-8.02 (m, 2H, ArH).

<Example 102> Ethylacetyl(2-(2-hydroxy-4-isopropylphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)carbamate

9b-chrolo-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one(0.70 g, 2.07 mmol) was dissolved in anhydrous THF (15 ml). Thissolution was added with Ethyl chroloformate (0.32 g, 3.11 mmol) andTrimethylamine (0.25 g, 2.48 mmol). The reaction mixture was stirred for4 hrs. After concentrating in a vacuum to remove THF, and the remainderwas diluted with Methylene chloride and washed with water many times.After drying and filtrating, the organic layer was purified using columnchromatography(ethylacetate:hexane=1:4) to afford the title compound(0.64 g, 71%).

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (d, J=6.9 Hz, 6H, CH₃) 1.46 (t, J=7.1 Hz,3H, CH₃) 2.03 (s, 3H, CH₃) 2.83-2.88 (m, 1H, CH) 4.31-4.38 (q, J=7.1 Hz,2H, OCH₂) 6.67 (s, 1H, NH) 6.92 (s, 1H, ArH) 7.12 (dd, J=1.2, 8.2 Hz,1H, ArH) 7.43 (d, J=8.2 Hz, 1H, ArH) 7.81-7.84 (m, 2H, ArH) 7.96-7.99(m, 2H, ArH).

<Example103>2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylethylcarbamate

2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylethylcarbamate (0.27 g, 0.59 mmol) was dissolved in Ethanol (10 ml) andwater (1 ml). This solution was added with iron (0.24 g, 4.3 mmol) andconc. HCl (0.03 ml). The reaction mixture was heated for 2 hrs underreflux. After filtrating and washing with MeOH, the remainder wasconcentrated in a vacuum and purified using columnchromatography(ethylacetate:hexane=1:1) to afford the title compound (90mg, 36%).

¹H-NMR (300 MHz, CDCl₃) δ 1.11-1.92 (d, J=6.9 Hz, 6H, CH₃) 1.95 (s, 3H,CH₃) 2.79-2.88 (m, 1H, CH) 3.10-3.26 (m, 2H, CH₃) 5.24 (s, 1H, NCH) 5.56(s, 2H, NH₂) 6.21 (s, 1H, NH) 6.60 (d, J=8.4 Hz, 1H, ArH) 6.71 (s, 1H,ArH) 6.88 (d, J=7.8 Hz, 1H, ArH) 7.06 (d, J=7.5 Hz, 1H, ArH) 7.42 (t,J=7.8 Hz, 2H, ArH).

<Example 104>2-(3-Methoxyphenyl)-2H-inden-1,3-dione

Sodium (1.1 g) was dissolved in anhydrous Ethanol (90 ml). This solutionwas added with Phthalide (4.43 g, 33.04 mmol) and m-Methoxy benzaldehyde(3.00 g, 22.03 mmol). The reaction mixture was heated for 3 hrs underreflux. The reaction mixture was concentrated in a vacuum. White solidwas obtained by adding conc. HCl. And then the white solid wasrecrystallized in ethylacetate:hexane (=1:2) to afford the titlecompound (2.45 g, 44%).

¹H-NMR (300 MHz, CDCl₃) δ 3.78 (s, 3H, OCH₃) 6.73-6.76 (m, 2H, ArH) 6.85(d, J=7.2 Hz, 1H, ArH) 7.26 (t, J=7.8 Hz, 1H, ArH) 7.89-7.93 (m, 2H,ArH) 8.06-8.09 (m, 2H, ArH).

<Example 105> ethyl (6-(2-((ethoxycarbonyl)oxy)-4-isopropylphenyl)-5,7-dioxo-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)carbonate

4b,9b-dihydroxy-7-isopropyl-4bH-benzofuro[2′,3′:3,4]cyclopenta[1,2-b]pyridin-10(9bH)-one(0.50 g, 1.68 mmol) was dissolved in THF (10 ml) and Et₃N (0.70 ml, 5.04mmol). This solution was added with Ethyl chroloformate (0.40 ml, 4.20mmol). The reaction mixture was stirred for 2 hrs. After concentratingin a vacuum, and the remainder was purified using columnchromatography(ethylacetate:hexane=1:2) to afford the title compound(0.20 g, 27%).

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (d, J=6.8 Hz, 6H), 1.28 (t, J=7.2 Hz,3H), 1.32 (t, J=7.6 Hz, 3H), 2.87 (q, J=7.1 Hz, 1H), 4.10-4.18 (m, 4H),6.92 (s, 1H), 6.20 (dd, J=1.1 Hz, 8.4 Hz, 1H), 7.73-7.79 (m, 2H), 8.33(d, J=7.9 Hz, 1H), 9.16 (d, J=4.7 Hz, 1H).

<Example 106>N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethoxyphenyl)isobutyramide

Ninhydrin (1.00 g, 5.6 mmol) was dissolved in conc. H₂SO₄(10 ml). Thissolution was added with N-(3,4-dimethoxyphenyl)isobutyramide (1.25 g,5.62 mmol) at 0° C. and stirred for 30 min under room temperature. Icewater was added with the reaction mixture, and then washed with icewater and ethylacetate. After drying and filtrating, the ethylacetatelayer was purified using column chromatography(ethylacetate:hexane=1:4)to afford the title compound (1.37 g, 63%).

¹H-NMR (300 MHz, CDCl₃) δ 1.28 (d, J=6.9 Hz, 6H, CH₃) 2.63-2.72 (m, 1H,CH) 3.56 (s, 3H, OCH₃) 3.86 (s, 3H, OCH₃) 5.84 (s, 1H, ArH) 6.87 (s, 1H,ArH) 7.99-8.04 (m, 2H, ArH) 8.13-8.18 (m, 2H, ArH).

<Example 107> N-[2-(4-Amino-2-hydroxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide

N-[2-(2-hydroxy-4-nitro-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide(150 mg, 0.35 mmol) was dissolved in ethanol (3 ml) and water (0.3 ml).This solution was added with iron (Fe) (0.14 g, 2.55 mmol) and conc. HCl(0.03 ml), followed by heating for 3 hrs under reflux. The reactionmixture was filtrated with MeOH washing via celite pad, and the filtratewas concentrated in a vacuum. The concentrated organic layer waspurified using column chromatography (ethylacetate:hexane=1:4) to affordthe title compound (17 mg, 12%).

¹H-NMR (300 MHz, CDCl₃) δ 0.77 (d, J=6.9 Hz, 3H, CH₃) 1.19 (d, J=6.9 Hz,3H, CH₃) 2.01-2.10 (m, 1H, CH), 3.91 (s, 3H, OMe) 4.07 (s, 3H, OMe) 5.36(s, 2H, NH₂) 6.49 (d, J=7.2 Hz, 1H, ArH) 6.74 (d, J=8.1 Hz, 1H, ArH)7.15 (s, 1H, ArH) 7.37 (t, J=7.5 Hz, 1H, ArH) 8.35 (s, 1H, ArH).

<Example 108>N-[2-(2-Hydroxy-5,6-dimethoxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide

5,6-dimethoxy-indan-1-one (3.0 g, 15.6 mmol) was dissolved in anhydrousdioxane (30 ml). This solution was added with SeO2 (3.80 g, 34.3 mmol)and acetic acid (3 ml), followed by heating for 5 hrs under reflux. Thereaction mixture was filtrated with MeOH washing via celite pad, and thefiltrate was concentrated in a vacuum to remove solvent. The remainder(2.13 g, 8.95 mmol) was dissolved in conc. H2SO4(20 ml), and added withisobutyramide (3.50 g, 15.6 mmol), followed by stirring for 2 hrs underroom temperature. After stirring, the reaction mixture was washed withethylacetate and water in several times. The obtained organic layer wasdried, filtrated and concentrated in a vacuum. The concentrated organiclayer was purified using column chromatography (ethylacetate:hexane=1:4)to afford the title compound (218 mg, 3%).

¹H-NMR (300 MHz, CDCl₃) δ 1.36 (d, J=6.6 Hz, 6H, CH₃) 2.67-2.76 (m, 1H,CH) 3.63 (s, 3H, OMe) 3.85 (s, 3H, OMe) 4.06 (s, 6H, OMe) 6.24 (s, 1H,ArH) 7.15 (s, 1H, ArH) 7.99 (s, 1H, ArH) 9.70 (s, 1H, ArH).

In Table 1, chemical formulas of compounds of examples 1 to 108 areshown.

TABLE 1 Ex. Chemical structure  1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

<Experimental Example 1> Cytopathic Effect (CPE) Inhibition Assay forAntiviral Activity Against Picornaviruses

In the assay, HeLa (human cervical cancer cells), MRC-5 (human fetallung fibroblast cells), and RD cells (derived from humanrhabdomyosarcoma) were employed. For comparison, ribavirin (Riv),pleconaril (pleco), and BTA-798 (BTA) were used as controls. Reagentswere dissolved at a concentration of 10˜40 mg/ml in 100%dimethylsulfoxide (DMSO). Water-soluble reagents were dissolved in PBS(−) solution and stored at −20° C. On the day of the experiment, theywere used in 3× to 5× concentrations in such a manner that theconcentration of dimethylsulfoxide in each well was between 0.5% and 1.

Pharmaceutical effects were determined using a virus-induced cytopathiceffect (CPE) inhibition assay. In this regard, after cells suitable forviruses were grown in 96-well plates, dilutions of viruses in DMEsupplemented with 2% FBS (DME/2% FBS) or MEM supplemented with 2% FBS(MEM/2% FBS) were inoculated in an amount of 100 μl with a concentrationcorresponding to 100 CCID₅₀(50% cell culture infective dose) into eachwell of the plates, and incubated for 30 min˜1 hrs at 33° C. or 37° C.to allow the viruses to adosorb to the cells. The culture medium wasremoved before aliquots of drug dilutions with various concentrationswere added in an amount of 100 μl to each well. While HRV was grown at33° C., the other viruses were incubated in a 37° C. CO₂ incubator for2˜3 days. Alternatively, the cells were cultured for 2˜3 days withoutremoval of the medium after they were added with 50 μl of each drugdilution having a 2-fold higher concentration and then with 50 μl of thevirus dilution.

Test conditions for each virus are summarized in Table 2, below.

TABLE 2 Host Incubation Incubation Virus Note cell Temp. Term MediumCoxsackie — RD 37° C. 2 days MEM/2% A9 FBS Coxsackie — MRC-5 37° C. 2days MEM/2% A24 FBS Coxsackie Isolated MRC-5 37° C. 2 days MEM/2% A24from FBS patients Coxsackie — HeLa 37° C. 2 days DME/2% B1 FBS Coxsackie— HeLa 37° C. 2 days DME/2% B3 FBS Coxsackie — HeLa 37° C. 2 days DME/2%B4 FBS Entero 70 — MRC-5 37° C. 2 days MEM/2% FBS Poliovirus3 — HeLa 37°C. 2 days DME/2% FBS Rhinovirus — HeLa 33° C. 3 days MEM/2% FBS

For HeLa cells, the drugs were measured for EC₅₀ (50% maximal effectiveconcentration), which is the concentration of a drug inducing a responsehalfway between the baseline and maximun, using an MTT assay. Withregard to RD and MRC-5 cells, CPE was determined using FDA (Fluoresceindiacetate). In order for the evaluation results of drug potency toreflect the toxic effect of the drug, mock-infected cells which wereprepared by adding a virus-free medium to a cell culture were treated inthe same manner. That is, the medium was removed after one hour ofincubation, and dilutions of drugs in the medium were added once more.Following incubation for 2 3 days, the cells were observed under amicroscope and the drugs were determined for CC₅₀(50% cytotoxicconcentration), using an MTT assay in which counts of viable cells inmock-infected wells containing drugs were compared to those of viablecells in control wells containing no drugs. In an FDA hydrolysis assay,FDA was added to each well after removal of the medium, and incubatedfor 20˜30 min before fluorescence intensity was measured using aspectrofluorometer to determine CPE in the same manner as in MTT.

Survival rate (% survival) of mock-infected cells was calculated usingthe following Mathmatic Formula 1:

$\begin{matrix}{{{Cell}\mspace{14mu}{Survival}\mspace{14mu}{by}\mspace{14mu}{Drug}} = {\frac{{A({Drug})} - {A\left( {{Background}\mspace{14mu}{{Sol}'}n} \right)}}{\begin{matrix}{{A\left( {{Cell}\mspace{14mu}{Control}} \right)} -} \\{A\left( {{Background}\mspace{14mu}{{Sol}'}n} \right)}\end{matrix}} \times 100\%}} & \left\lbrack {{Mathmatic}\mspace{14mu}{Formula}\mspace{14mu} 1} \right\rbrack\end{matrix}$

While 100% cell survival means no cytotoxicity of the drug, the highestcytotoxicity is reflected by 0% cell survival. The 50% cytotoxicconcentration (CC₅₀) was defined as the concentration required to reducethe cell number by 50% compared to that for the untreated controls.Higher CC₅₀ values mean lower cytotoxicity.

In addition, antiviral effects can be calculated using the followingMathmatic Formula 2:

$\begin{matrix}{{{Antiviral}\mspace{14mu}{Effect}} = {\frac{{A\left( {{Drug}\text{/}{Virus}} \right)} - {A\left( {{Virus}\mspace{14mu}{Control}} \right)}}{{A\left( {{Cell}\mspace{14mu}{Control}} \right)} - {A\left( {{Virus}\mspace{14mu}{Control}} \right)}} \times 100\%}} & \left\lbrack {{Mathmatic}\mspace{14mu}{Formula}\mspace{14mu} 2} \right\rbrack\end{matrix}$

A survival rate of 100% means a perfect antiviral effect (100%) whereasthe drugs are regarded to be devoid of antiviral effects at a survivalrate of 0%. The viral cytopathic effect (CPE) was recorded, and the 50%effective concentration (EC₅₀) was defined as the compound concentrationrequired to reduce the viral CPE by 50% compared to that for theuntreated control. Lower EC₅₀ values mean higher antiviral activities.

CC₅₀ and EC₅₀ values of the compounds which account cytotoxicity andantivival activity against picornaviruses, respectively, are given inTables 3 and 4.

TABLE 3 EC₅₀ (μg/mL) Coxsackie- Coxsackie- Polio- Polio- Entero- Ex.CC₅₀ Coxsackie- Coxsackie- Coxsackie- virus virus virus virus virus No.(μg/mL) virus B1 virus B3 virus B4 A24 (DN) A24 (HG) 3 2 70 1 >100 — — —— — — — — 2 >100 — — — — — — — <1.0  3 50.7 — — — — — — —  0.013 4 50.4— — — — — — — — 5 26 — — — — — — — — 6 23.5 <0.01  0.035 — — — — — <0.017 >100 — — — — — — — — 8 7.91 — — — — — — — — 9 >100 — — — — — — — — 107.85 — — — — — — — — 11 8.42 — — — — — — — — 12 74.12 — — — — — — — — 137.93 — — — — — — — — 14 8.26 — — — — — — — — 15 8.26  0.015 — — — — — —— 16 8.87 — — — — — — — — 17 9.3 — — — — — — — — 18 >100 — — — — — — — —19 17.7 <0.01 <0.01 — — <1.0 <1.0 — <0.01 20 >100 — — — — — — — — 21 16<0.01 — — — — — — — 22 33.8 <0.01 — — — — — — — 23 44.3 <0.01 — — — — —— — 24 >100 — — — — — — — — 25 >100 — — — — — — — — 26 >100 — — — — — —— — 27 9.5 — — — — — — — — 28 9.2 — — — — — — — — 29 >100 — — — — — — —— 30 >100 <0.01 — — — — — — — 31 >100 — — — — — — — — 32 28.69 <0.01 — —— — — — — 33 >100 — — — — — — — — 34 46.25 — — — — — — — — 35 59.8 — — —— — — — — 36 9.42 <0.01 <0.01 — <0.1 <0.01 <0.01 — — 37 62.72 — — — — —— — — 38 >100 — — — — — — — — 39 6.67 — — — — — — — — 40 53.25 — — — — —— — — 41 — — — — — — — — — 42 71.06 — — — — — — — — 43 61.7 — — — — — —— — 44 >117 — — — — — — — — 45 >117 — — — — — — — — 46 63.98 — — — — — —— — 47 50.92 — — — — — — — — 48 46.74 <0.01 <0.01 — — — — — — 49 >100<0.01 <0.01 <0.01 <1.0 <1.0 <1.0 <1.0 — 50 44.32    0.0112 — — — — — — —51 9.34 — — — — — — — — 52 27.67 — — — — — — — — 53 10.2 — — — — — — — —54 >117    0.0198 — — — — — — — 55 >117 — — — — — — — — 56 87.77 — — — —— — — — 57 48.21 — — — — — — — — 58 47.79 — — — — — — — — 59 53.67 — — —— — — — — 60 68.93 — — — — — — — — 61 >117 — — — — — — — — 62 11.26 — —— — — — — — 63 >117 — — — — — — — — 64 87.77 — — — — — — — — 65 11.16 —— — — — — — — 66 26.69 — — — — — — — — 67 54.59 — — — — — — — — 68 65.95<0.01 <0.01 — — <1.0 — — — 69 >117 <0.01 <0.01 — <1.0 <1.0 <1.0 — —70 >117 <0.01 <0.01 — — <1.0 — — — 71 >100 — — — — — — — — 72 >100 — — —— — — — — 73 >100 — — — — — — — — 74 — — — — — — — — — 75 >100 — — — — —— — —

TABLE 4 Coxsackie-virus Coxsackie-virus Picorna-virus B1 B3 Polio-virus3 Ex. CC₅₀ EC₅₀ EC₅₀ EC₅₀ No. (μg/mL) (μg/mL) (μg/mL) (μg/mL) 76 45.11<0.01 <0.04 — 77 77.77 0.014  0.018 — 78 68.17 <0.01 <0.01 — 79 8.94<0.01 <0.01 — 80 >100 <0.01 <0.01 — 81 41.26 <0.01 <0.01 0.012 82 >100<0.01 <0.02 0.015 83 >100 <0.01 <0.01 — 84 >100 <0.01 <0.01 — 85 45.85<0.01 <0.03 0.015 86 4.63 — — — 87 8.31 0.019 — — 88 4.49 — — — 89 10.7— — — 90 38.26 — — — 91 40.02 0.015 — — 92 43.58 <0.01 <0.01 — 93 35.21<0.01 <0.01 — 94 39.17 <0.01 <0.01 — 95 27.45 <0.01 <0.01 — 96 48.85<0.01 <0.01 0.03  97 45.09 <0.01 <0.01 — 98 >100 0.013 — — 99 38.07<0.01 <0.01 — 100 >100 <0.01 <0.01 — 101 45.95 <0.01 <0.01 — 102 42.5<0.01 <0.01 — 103 26.27 <0.01 <0.01 0.013 104 >100 — — — 105 >100 — — —106 >100 — — — 107 >100 — — — 108 >100 — — —

As is understood from data of Tables 3 and 4, most of the1,3-Dioxoindene derivatives of the present invention exhibited lowcytotoxicity because they had high CC₅₀ values. In addition, most of the1,3-Dioxoindene derivatives of the present invention were found to behighly inhibitory of coxsackie-, polio-, rhino-, and entero-virusesbecause their EC₅₀ values were 0.01 μg/mL or less.

Accordingly, the 1,3-Dioxoindene derivatives represented by ChemicalFormula 1 in accordance with the present invention exhibit lowcytotoxicity and high inhibitory activity against a broad spectrum ofpicornaviruses, and thus may be usefully applied to a pharmaceuticalcomposition for preventing or treating picornavirus-caused diseases.

<Experimental Example 2> Multicycle Cytopathic Effect (CPE) ReductionAssay for Antiviral Effect against Picornaviruses

The test compounds were evaluated for anti-picornavirus activity by amulticycle cytopathic effect (CPE) reduction assay. The antiviralactivity was initially determined using an MTS[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]-basedCPE reduction assay.

In this regard, cells grown to confluence in 96-well plates wereinfected with 100 50% cell culture infective doses (CCID₅₀) of virus.After an adsorption period of 2 hrs at 37° C., virus was removed andserial dilutions of the compounds were added. The cultures were furtherincubated at 37° C. for 3 days, until complete CPE was observed in theinfected and untreated virus control (VC). After removal of the medium,90 μl of a culture medium and 10 μl of MTS-phenazine methosulfate(Promega, Leiden, The Netherlands) were added to each well. After anincubation period of 2 hrs at 37° C., the optical density (OD) of eachwell was read at 498 nm in a microplate reader.

CPE values for evaluating antiviral activity were calculated using thefollowing Mathmatic Formula 3:

$\begin{matrix}{{\%\mspace{14mu}{CPE}} = {100 \times \frac{{OD}_{CC} - {OD}_{{virus} + {compound}}}{{OD}_{CC} - {OD}_{VC}}}} & \left\lbrack {{Mathmatic}\mspace{14mu}{Formula}\mspace{14mu} 3} \right\rbrack\end{matrix}$

CPE values for evaluating cytotoxicity were calculated using thefollowing Mathmatic Formula 4:

$\begin{matrix}{{\%\mspace{14mu}{CPE}} = {100 \times \frac{{OD}_{CC} - {OD}_{compound}}{{OD}_{CC} - {OD}_{Blank}}}} & \left\lbrack {{Mathmatic}\mspace{14mu}{Formula}\mspace{14mu} 4} \right\rbrack\end{matrix}$

In Formulas 3 and 4,

OD_(CC) corresponds to the OD of the uninfected and untreated,background cell cultures,

OD_(VC) represents the OD of the infected and untreated control cellcultures,

OD_(virus+Compound) represents the OD of the virus-infected cellcultures treated with a given concentration of compound, and

ODBlank represents the OD of the well added with the cell culture mediumalone.

The 50% effective concentration (EC₅₀) and the 50 cytotoxicconcentration (CC₅₀) were defined as the concentrations of compound thatoffered 50% protection against virus-induced CPE and that killed cellsby 50%, respectively, and were calculated using logarithmicinterpolation.

CC₅₀ and EC₅₀ against various viruses of some compounds are given inTable 3, below.

TABLE 5 Ex. 19 Ex. 36 Ex. 74 CC₅₀ [μM] >100 >50 >100 Coxsackie B3^(c)EC₅₀ <0.01 <0.01 — [μM] Coxsackie A16^(d) 0.064 ± 0.010  —   13 ± 0.32EC₅₀ [μM] Coxsackie A9^(f) EC₅₀ — 0.0070 ± 0.00018 — [μM] CoxsackieA21^(d) 0.67 ± 0.13  —   26 ± 0.34 EC₅₀ [μM] Entero 71^(e) EC₅₀  0.10 ±0.0018 0.0067 ± 0.00078 3.3 ± 1.6 [μM] Echo 9^(d) EC₅₀ [μM] 0.017 ±0.0067 0.011 ± 0.0032  0.61 ± 0.038 Echo 11^(f) EC₅₀ [μM] 0.017 ± 0.00780.0082 ± 0.0019  0.70 ± 0.24 Polio 1^(f) EC₅₀ [μM] 0.79 ± 0.36  0.22 ±0.050 20 ± 14 Polio 2^(f) EC₅₀ [μM] — — — Polio 3^(f) EC₅₀ [μM] <1.0<0.01 — Rhino 2^(g) EC₅₀ [μM] >50 7.8 ± 0.57 >50 Rhino 9^(g) EC₅₀[μM] >50 1.2 ± 0.12 >50 Rhino 15^(g) EC₅₀ >50 1.5 ± 0.24 >50 [μM] Rhino29^(g) EC₅₀ >50 5.5 ± 0.72 >50 [μM] Rhino 39^(g) EC₅₀ >50 1.4 ± 0.20 >50[μM] Rhino 41^(g) EC₅₀ >50  0.54 ± 0.0030 >50 [μM] Rhino 45^(g) EC₅₀ 4.6 ± 0.0083 <0.078^(i) >50 [μM] Rhino 59^(g) EC₅₀ — — >50 [μM] Rhino63^(g) EC₅₀ >50 >10 >50 [μM] Rhino 85^(g) EC₅₀ >50 7.5 ± 1.2  >50 [μM]Rhino 89^(g) EC₅₀ >50 0.49 ± 0.038 >50 [μM] Rhino 14^(g) EC₅₀ 0.45 ±0.41  0.35 ± 0.32  >50 [μM] Rhino 42^(g) EC₅₀ >50 — >50 [μM] Rhino70^(g) EC₅₀ 2.0 ± 0.12 >0.078^(i) >50 [μM] Rhino 72^(g) EC₅₀  4.6 ±0.092 — >50 [μM] Rhino 86^(g) EC₅₀ 26 ± 18  — 26 ± 18 [μM]

In Table 5, the superscript c represents incubation at 37° C. in Verocells, the superscript d represents incubation at 37° C. in MRC-5 cells,the superscript e represents incubation at 37° C. in RD cells, thesuperscript f represents incubation at 37° C. in BGM cells, thesuperscript g represents incubation at 37° C. in HeLa cells, and thesuperscript i represents 100% inhibition of viral replication withcompounds of 0.078 μM or higher.

As can be seen in Table 5, the 1,3-Dioxoindene derivatives according tothe present invention are low in cytotoxicity because their CC₅₀ wasmeasured at 50 μM or higher, especially the compound of EXAMPLE 19 andEXAMPLE 74 are low in cytotoxicity because their CC₅₀ was measured at100 μM or higher. In addition, the 1,3-Dioxoindene derivatives wereobserved to have an EC₅₀ of 26 μM or less against coxsackieviruses B3,A16, A9, and A21. Particularly high antiviral activity was detected inthe compound of EXAMPLE 19 and EXAMPLE 36 with an EC₅₀ of as low as 0.01μM.

With regard to enterovirus 71, the 1,3-Dioxoindene derivatives accordingto the present invention showed an EC₅₀ of 3.3 μM or less. Particularlyhigh antiviral activity was detected in the compound of EXAMPLE 36 withan EC₅₀ of as low as 0.0067 μM.

The 1,3-Dioxoindene derivatives according to the invention showed anEC₅₀ of 0.70 μM or less against echovirus 9 and echovirus 11, while thehighest antiviral activity was detected in the compound of EXAMPLE 36 asdemonstrated by the EC₅₀ of 0.0082 μM.

In the case of polioviruses 1, 2 and 3, EC₅₀ values of the1,3-Dioxoindene derivatives according to present invention were measuredto be 20 μM or less. Particularly high antiviral activity was detectedin the compound of EXAMPLE 36 with an EC₅₀ of as low as 0.01 μM.

Also, the 1,3-Dioxoindene derivatives according to the invention werehighly inhibitory of rhinoviruses. For example, EC₅₀ of 50 μM or morewas detected against rhinoviruses 2, 9, 15, 29, 39, 41, 45, 59, 63, 85,89, 14, 42, 70, 72, and 86. Particularly high antiviral activity wasdetected in the compound of EXAMPLE 36 with an EC₅₀ of 0.078 μM or lessagainst rhinoviruses 45 and 70.

Consequently, the 1,3-Dioxoindene derivatives of the present inventionare of low cytotoxicity and exhibit excellent antiviral activity againstpicornaviruses including coxsackie-, entero-, echo-, polio- andrhinoviruses, so that they can be usefully applied to the prevention ortreatment of picornavirus-caused respiratory, cardiocirculatory, andnervous system diseases, including poliomyelitis, paralysis, acutehemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouthdisease, vesicular disease, hepatitis A, myositis, myocarditis,pancreatitis, diabetes, epidemic myalgia, encephalitis, cold,herpangina, foot-and-mouth disease, asthma, chronic obstructivepulmonary disease, pneumonia, sinusitis and otitis media.

<Formulation Example 1> Preparation of Pharmaceutical Formulations

<1-1> Preparation of Powder

1,3-Dioxoindene derivative: 2 g Lactose: 1 g

The above ingredients were mixed and loaded into an airtight sac toproduce a powder agent.

<1-2> Preparation of Tablet

1,3-Dioxoindene derivative: 100 mg Corn starch: 100 mg Lactose: 100 mgMg stearate:  2 mg

These ingredients were mixed and prepared into tablets using a typicaltabletting method.

<1-3> Preparation of Capsule

1,3-Dioxoindene derivative: 100 mg Corn starch: 100 mg Lactose: 100 mgMg stearate:  2 mg

These ingredients were mixed and loaded into gelatin capsules accordingto a typical method to produce capsules.

<1-4> Preparation of Injection

1,3-Dioxoindene derivative: 10 μg/ml Diluted Hydrochloric acid BP: to bepH 3.5 Sodium chloride BP for injection: maximum 1 ml

The 1,3-Dioxoindene derivative of the present invention was dissolved ina appropriate volume of sodium chloride BP for injection. The pH of theresultant solution was regulated to be pH 3.5 with dil.HCl BP, and thenits volume was regulated with sodium chloride BP for Injection and thesolution was mixed completely. The solution was then filled in 5-ml type1 ample that is made of transparent glass. The air was sealed in upperlattice by melting the glass. The solution contained in ample wasautoclaved at 120° C. for 15 min or more to be sterilized and thereby toobtain an injection.

INDUSTRIAL APPLICABILITY

Having excellent inhibitory activity against picornaviruses includingcoxsackie-, entero-, echo-, Polio-, and rhinoviruses, as well asexhibiting low cytotoxicity, as described hitherto, the 1,3-Dioxoindenederivative of Chemical Formula 1 can be useful as an active ingredientof a pharmaceutical composition for the prevention or treatment of viraldiseases including poliomyelitis, paralysis, acute hemorrhagicconjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesiculardisease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes,epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouthdisease, asthma, chronic obstructive pulmonary disease, pneumonia,sinusitis or otitis media.

The invention claimed is:
 1. A compound of Formula 1, or apharmaceutically-acceptable salt or optical isomer thereof:

where, A¹ is —NH₂; A², A³ and A⁴ are, independently any one selectedfrom a group consisting of —H, halogen, —OH, —CN, —N₃, C₁-C₁₀ alkoxy,C₁-C₁₀ straight- or branched-chain alkyl, C₆-C₁₂ aryl, —O(C═O)R¹,—(C═O)R¹, —(C═O)OR¹, —O(C═O)OR¹, —O(C═O)NR¹R², —NO₂, —NR¹R²,—NR¹(C═O)R², —NR¹(C═S)R², —NR¹(C═O)OR², —NR¹(C═O)—NR²R³ and—NR¹(C═S)—NR²R³, or two or more neighboring substituents A², A³ and A⁴may form a ring together, wherein a ring formed by two or moreneighboring substituents A², A³ and A⁴ may include one or more heteroatom, and the hetero atom is N, O or S; G is halogen, —OH, —CN, —N₃,C₁-C₁₀ alkoxy, —O(C═O)R¹, —(C═O)R¹, —(C═O)OR¹, —O(C═O)OR¹, —O(C═O)NR¹R²,—NO₂, —NR¹R², —NR¹(C═O)R², —NR¹(C═S)R², —NR¹(C═O)OR², —NR¹(C═O)—NR²R³,—NR¹(C═S)—NR²R³ or

D¹, D², D³ and D⁴ are independently selected from a group consisting of—H, halogen, —OH, —CN, C₁-C₁₀ alkoxy, C₁-C₁₀ straight- or branched-chainalkyl, C₆-C₁₂ aryl, —(CH₂)_(n)—(C═O)OR¹, —O(C═O)R¹, —(C═O)R¹, —(C═O)OR¹,—O(C═O)OR¹, —O(C═O)NR¹R², —NO₂, —NR¹R², —NR¹(C═O)R², —NR¹(C═S)R²,—NR¹(C═O)OR², —NR¹(C═O)—NR²R³, —SR¹ and —NR¹(C═S)—NR²R³, or two or moreneighboring substituents D¹, D², D³ and D⁴ may form a ring together, aring formed by two or more neighboring substituent D¹, D², D³ and D⁴ mayinclude one or more hetero atom, and the hetero atom is N, O or S; E is—H, —OH, —OR¹, —O(C═O)R¹, —(C═O)R¹, —(C═O)OR¹, —O(C═O)OR¹, —O(C═O)NR¹R²,—NO₂, —NR¹R², —NR¹(C═O)R², —SR¹, —NR¹(C═S)R², —NR¹(C═O)OR²,—NR¹(C═O)—NR²R³ or —NR¹(C═S)—NR²R³; R¹, R² and R³ are, eachindependently, hydrogen, nonsubstituted or phenyl-substituted C₁-C₁₀straight- or branched-chain alkyl, C₁-C₁₀ alkoxy, nonsubstituted orphenyl-substituted C₁-C₁₀ straight- or branched-chain alkenyl, C₃-C₇cycloalkyl or nonsubstituted or phenyl-substituted C₆-C₁₂ aryl; X and Yare, each independently, hydrogen, oxygen, hydroxy or sulfur; Z¹, Z² andZ³ are carbon or nitrogen; n is integer between 1-10; and ‘

’ denotes single or double bond.
 2. The compound of claim 1, or apharmaceutically-acceptable salt or optical isomer thereof where, A², A³and A⁴ are independently any one selected from a group consisting of —H,halogen, —OH, —CN, —N₃, C₁-C₁₀ alkoxy, C₁-C₁₀ straight- orbranched-chain alkyl, C₆-C₁₂ aryl, —O(C═O)R¹, —(C═O)R¹, —(C═O)OR¹,—O(C═O)OR¹, —O(C═O)NR¹R², —NO₂, —NR¹R², —NR¹(C═O)R², —NR¹(C═S)R²,—NR¹(C═O)OR², —NR¹(C═O)—NR²R³ and —NR¹(C═S)—NR²R³; G is halogen, —OH,—CN, —N₃, C₁-C₁₀ alkoxy, —O(C═O)R¹, —O(C═O)OR¹, —O(C═O)NR¹R²,—NR¹(C═O)R², —NR¹(C═O)OR², —NR¹(C═O)—NR²R³, or

D¹, D², D³ and D⁴ are independently selected from a group consisting of—H, halogen, —OH, —CN, C₁-C₁₀ alkoxy, C₁-C₁₀ straight- or branched-chainalkyl, C₆-C₁₂ aryl, —(CH₂)_(n)—(C═O)OR¹, —O(C═O)R¹, —(C═O)R¹, —(C═O)OR¹,—O(C═O)OR¹, —O(C═O)NR¹R², —NO₂, —NR¹R², —NR¹(C═O)R², —NR¹(C═S)R²,—NR¹(C═O)OR², —NR¹(C═O)—NR²R³, —SR¹ and —NR¹(C═S)—NR²R³; E is —OH, —OR¹,—O(C═O)R¹, —O(C═O)OR¹, or —O(C═O)NR¹R²; X and Y are, each oxygen; Z¹, Z²and Z³ are carbon; n is an integer between 1-10; and ‘

’ denotes a double bond.
 3. The compound of claim 1, or apharmaceutically-acceptable salt or optical isomer thereof, wherein, A²,A³ and A⁴ are selected from a group consisting of —H, halogen, C₁-C₁₀straight- or branched-chain alkyl, —NR¹R², and —NR¹(C═O)R²: G is —OH,—O(C═O)R¹, —O(C═O)OR¹, —NR¹(C═O)R², —NR¹(C═O)OR² or

D¹, D², D³ and D⁴ are independently selected from a group consisting ofhalogen, C₁-C₁₀ straight- or branched-chain alkyl, —NR¹(C═O)R²,—NR¹(C═O)OR² and —NR¹(C═O)—NR²R³; E is —OH, —OR¹, —O(C═O)R¹, —O(C═O)OR¹,or —O(C═O)NR¹R²; R¹, R² and R³ are, each independently, hydrogen,nonsubstituted or phenyl-substituted C₁-C₉ straight- or branched-chainalkyl, nonsubstituted or phenyl-substituted C₁-C₅ straight- orbranched-chain alkenyl or C₆-C₁₀ aryl; and n is an integer between 1-5.4. The compound of claim 1, or a pharmaceutically-acceptable salt oroptical isomer thereof, wherein A², A³ and A⁴ are independently selectedfrom a group consisting of —H, halogen, and —NR¹R²; G is —OH,—NR¹(C═O)R², or —NR¹(C═O)OR²; D¹, D², D³ and D⁴ are independentlyselected from the group consisting of halogen, C₁-C₁₀ straight- orbranched-chain alkyl, and —NR¹(C═O)R²; E is —OH, —OR¹, —O(C═O)R¹,—O(C═O)OR¹ or —O(C═O)NR¹R²; R¹, R² and R³ are, each independently,hydrogen, nonsubstituted or phenyl-substituted C₁-C₈ straight- orbranched-chain alkyl, nonsubstituted or phenyl-substituted C₁-C₄straight- or branched-chain alkenyl or C₆-C₁₀ aryl; and n is an integerbetween 1-3.
 5. The compound of claim 1, or apharmaceutically-acceptable salt or optical isomer thereof, wherein, A²,A³ and A⁴ are independently selected from a group consisting of —H and—NR¹R²; G is —NR¹(C═O)R²; D¹, D², D³ and D⁴ are hydrogen, C₁-C₁₀straight- or branched-chain alkyl; E is —O(C═O)R¹; R¹, R² and R³ are,each independently, hydrogen, or C₁-C₇ straight- or branched-chainalkyl; and n is an integer between 1˜3.
 6. The compound,pharmaceutically acceptable salt, or optical isomer of claim 1, whereinthe compound is selected from the group consisting of: Acetic acid2-(2-acetoxy-4-isopropyl-phenyl)-4-amino-1,3-dioxo-indan-2-yl ester;4-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;N-(7-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide;4,7-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;4,5-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;2-(4-Amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpentanoate;2-(4-Amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylhexanoate;2-(4-Amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylheptanoate;2-(4-Amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpropionate;2-(4-Amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutyrate;2-(4-Amino-2-octanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyloctanoate;2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutylcarbonate2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutyl carbonate;2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyldimethylcarbamate;2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylethylcarbamate; andN-[2-(4-Amino-2-hydroxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide.7. The compound, pharmaceutically acceptable salt, or optical isomer ofclaim 1, wherein the compound is selected from the group consisting of:Acetic acid2-(2-acetoxy-4-isopropyl-phenyl)-4-amino-1,3-dioxo-indan-2-yl ester;2-(4-Amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpentanoate;2-(4-Amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylhexanoate;2-(4-Amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylheptanoate;2-(4-Amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylpropionate;2-(4-Amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutyrate;2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutylcarbonate2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylbutyl carbonate;2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyldimethylcarbamate; and2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenylethylcarbamate.
 8. A method for preparing a compound of formula 1a:

or a pharmaceutically-acceptable salt or optical isomer thereof, whereinA¹, A², A³, A⁴, D¹, D², D³, D⁴, Z¹, Z² and Z³ are as defined in claim 1,and J and L are, independently, identical to A¹, A², A³, A⁴, D¹, D², D³or D⁴; comprising acylating or alkylating a compound of formula 2:

in the presence of a base and a solvent to afford the compound offormula 1a.
 9. A method for preparing a compound of formula 1b:

or a pharmaceutically acceptable salt or optical isomer thereof, whereinA¹, A², A³, A⁴, D¹, D², D³, D⁴, Z¹, Z² and Z³ are as defined in Formula1 of claim 1, and J and L are, independently, identical to A¹, A², A³,A⁴, D¹, D², D³ or D⁴; comprising: treating a compound of Formula 2:

with thionyl chloride or oxalic chloride in the presence of a reactingbase and a solvent, and then treating the resulting mixture with ammoniato afford a compound of formula 3:

and acylating or alkylating the compound of formula 3 in the presence ofa base and a solvent to afford the compound of formula 1b.
 10. Apharmaceutical composition comprising the compound, pharmaceuticallyacceptable salt, or optical isomer of claim 1 and a pharmaceuticallyacceptable diluent or excipient.
 11. A method for preventing or treatinga viral disease in a patient, wherein the viral disease is caused by aCoxsackie virus, a polio virus, an echovirus, an enterovirus, arhinovirus, or a picornavirus comprising a ministering a therapeuticallyeffective amount of the compound, pharmaceutically acceptable salt, oroptical isomer of claim 1 to the patient.
 12. The method of claim 11,wherein the viral disease is caused by a Coxsackie virus.
 13. The methodof claim 11, wherein the viral disease is caused by a polio virus. 14.The method of claim 11, wherein the viral disease is caused by anechovirus.
 15. The method of claim 11, wherein the viral disease iscaused by an enterovirus.
 16. The method of claim 11, wherein the viraldisease is caused by a rhinovirus.
 17. The method of claim 11, whereinthe viral disease is caused by a picornavirus.
 18. The method of claim11, wherein the viral disease comprises: polio, acute hemorrhagicconjunctivitis, viral meningitis, hand-foot and mouth disease, swinevesicular disease (SVD), hepatitis A, myositis, viral myocarditis, viralpancreatitis, flu, herpangina, or foot and mouth disease.